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July 15, 2014; 83 (3) Article

Recurrent stroke predictors differ in medically treated patients with pathogenic vs other PFOs

David E. Thaler, Robin Ruthazer, Christian Weimar, Jean-Louis Mas, Joaquín Serena, Emanuele Di Angelantonio, Federica Papetti, Shunichi Homma, Heinrich P. Mattle, Krassen Nedeltchev, Marie-Luise Mono, Cheryl Jaigobin, Patrik Michel, Mitchell S.V. Elkind, Marco R. Di Tullio, Jennifer S. Lutz, John Griffith, David M. Kent
First published June 13, 2014, DOI: https://doi.org/10.1212/WNL.0000000000000589
David E. Thaler
From the Department of Neurology (D.E.T., D.M.K.) and the Predictive Analytics and Comparative Effectiveness Center, Institute for Clinical Research and Health Policy Studies (R.R., J.S.L., J.G., D.M.K.), Tufts Medical Center/Tufts University School of Medicine, Boston, MA; the University of Duisburg-Essen (C.W.), Germany; Hôpital Sainte-Anne (J.L.-M.), Paris-Descartes University, France; the Department of Neurology (J.S.), Hospital Universitari Doctor Josep Trueta Institut d'Investigació Biomèdica de Girona, Spain; the Department of Public Health and Primary Care (E.D.A.), Cambridge University, UK; the Department of Cardiology (F.P.), Sapienza University of Rome, Italy; the Departments of Cardiology (S.H.) and Neurology and Epidemiology (M.S.V.E.) and the Division of Cardiology (M.R.D.T.), Columbia University, New York; Inselspital (H.P.M., M.-L.M.), University of Bern; the Division of Neurology (K.N.), Triemli Municipal Hospital, Zurich, Switzerland; the University of Toronto (C.J.), Canada; and Centre Hospitalier Universitaire Vaudois (P.M.), Switzerland.
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Robin Ruthazer
From the Department of Neurology (D.E.T., D.M.K.) and the Predictive Analytics and Comparative Effectiveness Center, Institute for Clinical Research and Health Policy Studies (R.R., J.S.L., J.G., D.M.K.), Tufts Medical Center/Tufts University School of Medicine, Boston, MA; the University of Duisburg-Essen (C.W.), Germany; Hôpital Sainte-Anne (J.L.-M.), Paris-Descartes University, France; the Department of Neurology (J.S.), Hospital Universitari Doctor Josep Trueta Institut d'Investigació Biomèdica de Girona, Spain; the Department of Public Health and Primary Care (E.D.A.), Cambridge University, UK; the Department of Cardiology (F.P.), Sapienza University of Rome, Italy; the Departments of Cardiology (S.H.) and Neurology and Epidemiology (M.S.V.E.) and the Division of Cardiology (M.R.D.T.), Columbia University, New York; Inselspital (H.P.M., M.-L.M.), University of Bern; the Division of Neurology (K.N.), Triemli Municipal Hospital, Zurich, Switzerland; the University of Toronto (C.J.), Canada; and Centre Hospitalier Universitaire Vaudois (P.M.), Switzerland.
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Christian Weimar
From the Department of Neurology (D.E.T., D.M.K.) and the Predictive Analytics and Comparative Effectiveness Center, Institute for Clinical Research and Health Policy Studies (R.R., J.S.L., J.G., D.M.K.), Tufts Medical Center/Tufts University School of Medicine, Boston, MA; the University of Duisburg-Essen (C.W.), Germany; Hôpital Sainte-Anne (J.L.-M.), Paris-Descartes University, France; the Department of Neurology (J.S.), Hospital Universitari Doctor Josep Trueta Institut d'Investigació Biomèdica de Girona, Spain; the Department of Public Health and Primary Care (E.D.A.), Cambridge University, UK; the Department of Cardiology (F.P.), Sapienza University of Rome, Italy; the Departments of Cardiology (S.H.) and Neurology and Epidemiology (M.S.V.E.) and the Division of Cardiology (M.R.D.T.), Columbia University, New York; Inselspital (H.P.M., M.-L.M.), University of Bern; the Division of Neurology (K.N.), Triemli Municipal Hospital, Zurich, Switzerland; the University of Toronto (C.J.), Canada; and Centre Hospitalier Universitaire Vaudois (P.M.), Switzerland.
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Jean-Louis Mas
From the Department of Neurology (D.E.T., D.M.K.) and the Predictive Analytics and Comparative Effectiveness Center, Institute for Clinical Research and Health Policy Studies (R.R., J.S.L., J.G., D.M.K.), Tufts Medical Center/Tufts University School of Medicine, Boston, MA; the University of Duisburg-Essen (C.W.), Germany; Hôpital Sainte-Anne (J.L.-M.), Paris-Descartes University, France; the Department of Neurology (J.S.), Hospital Universitari Doctor Josep Trueta Institut d'Investigació Biomèdica de Girona, Spain; the Department of Public Health and Primary Care (E.D.A.), Cambridge University, UK; the Department of Cardiology (F.P.), Sapienza University of Rome, Italy; the Departments of Cardiology (S.H.) and Neurology and Epidemiology (M.S.V.E.) and the Division of Cardiology (M.R.D.T.), Columbia University, New York; Inselspital (H.P.M., M.-L.M.), University of Bern; the Division of Neurology (K.N.), Triemli Municipal Hospital, Zurich, Switzerland; the University of Toronto (C.J.), Canada; and Centre Hospitalier Universitaire Vaudois (P.M.), Switzerland.
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Joaquín Serena
From the Department of Neurology (D.E.T., D.M.K.) and the Predictive Analytics and Comparative Effectiveness Center, Institute for Clinical Research and Health Policy Studies (R.R., J.S.L., J.G., D.M.K.), Tufts Medical Center/Tufts University School of Medicine, Boston, MA; the University of Duisburg-Essen (C.W.), Germany; Hôpital Sainte-Anne (J.L.-M.), Paris-Descartes University, France; the Department of Neurology (J.S.), Hospital Universitari Doctor Josep Trueta Institut d'Investigació Biomèdica de Girona, Spain; the Department of Public Health and Primary Care (E.D.A.), Cambridge University, UK; the Department of Cardiology (F.P.), Sapienza University of Rome, Italy; the Departments of Cardiology (S.H.) and Neurology and Epidemiology (M.S.V.E.) and the Division of Cardiology (M.R.D.T.), Columbia University, New York; Inselspital (H.P.M., M.-L.M.), University of Bern; the Division of Neurology (K.N.), Triemli Municipal Hospital, Zurich, Switzerland; the University of Toronto (C.J.), Canada; and Centre Hospitalier Universitaire Vaudois (P.M.), Switzerland.
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Emanuele Di Angelantonio
From the Department of Neurology (D.E.T., D.M.K.) and the Predictive Analytics and Comparative Effectiveness Center, Institute for Clinical Research and Health Policy Studies (R.R., J.S.L., J.G., D.M.K.), Tufts Medical Center/Tufts University School of Medicine, Boston, MA; the University of Duisburg-Essen (C.W.), Germany; Hôpital Sainte-Anne (J.L.-M.), Paris-Descartes University, France; the Department of Neurology (J.S.), Hospital Universitari Doctor Josep Trueta Institut d'Investigació Biomèdica de Girona, Spain; the Department of Public Health and Primary Care (E.D.A.), Cambridge University, UK; the Department of Cardiology (F.P.), Sapienza University of Rome, Italy; the Departments of Cardiology (S.H.) and Neurology and Epidemiology (M.S.V.E.) and the Division of Cardiology (M.R.D.T.), Columbia University, New York; Inselspital (H.P.M., M.-L.M.), University of Bern; the Division of Neurology (K.N.), Triemli Municipal Hospital, Zurich, Switzerland; the University of Toronto (C.J.), Canada; and Centre Hospitalier Universitaire Vaudois (P.M.), Switzerland.
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Federica Papetti
From the Department of Neurology (D.E.T., D.M.K.) and the Predictive Analytics and Comparative Effectiveness Center, Institute for Clinical Research and Health Policy Studies (R.R., J.S.L., J.G., D.M.K.), Tufts Medical Center/Tufts University School of Medicine, Boston, MA; the University of Duisburg-Essen (C.W.), Germany; Hôpital Sainte-Anne (J.L.-M.), Paris-Descartes University, France; the Department of Neurology (J.S.), Hospital Universitari Doctor Josep Trueta Institut d'Investigació Biomèdica de Girona, Spain; the Department of Public Health and Primary Care (E.D.A.), Cambridge University, UK; the Department of Cardiology (F.P.), Sapienza University of Rome, Italy; the Departments of Cardiology (S.H.) and Neurology and Epidemiology (M.S.V.E.) and the Division of Cardiology (M.R.D.T.), Columbia University, New York; Inselspital (H.P.M., M.-L.M.), University of Bern; the Division of Neurology (K.N.), Triemli Municipal Hospital, Zurich, Switzerland; the University of Toronto (C.J.), Canada; and Centre Hospitalier Universitaire Vaudois (P.M.), Switzerland.
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Shunichi Homma
From the Department of Neurology (D.E.T., D.M.K.) and the Predictive Analytics and Comparative Effectiveness Center, Institute for Clinical Research and Health Policy Studies (R.R., J.S.L., J.G., D.M.K.), Tufts Medical Center/Tufts University School of Medicine, Boston, MA; the University of Duisburg-Essen (C.W.), Germany; Hôpital Sainte-Anne (J.L.-M.), Paris-Descartes University, France; the Department of Neurology (J.S.), Hospital Universitari Doctor Josep Trueta Institut d'Investigació Biomèdica de Girona, Spain; the Department of Public Health and Primary Care (E.D.A.), Cambridge University, UK; the Department of Cardiology (F.P.), Sapienza University of Rome, Italy; the Departments of Cardiology (S.H.) and Neurology and Epidemiology (M.S.V.E.) and the Division of Cardiology (M.R.D.T.), Columbia University, New York; Inselspital (H.P.M., M.-L.M.), University of Bern; the Division of Neurology (K.N.), Triemli Municipal Hospital, Zurich, Switzerland; the University of Toronto (C.J.), Canada; and Centre Hospitalier Universitaire Vaudois (P.M.), Switzerland.
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Heinrich P. Mattle
From the Department of Neurology (D.E.T., D.M.K.) and the Predictive Analytics and Comparative Effectiveness Center, Institute for Clinical Research and Health Policy Studies (R.R., J.S.L., J.G., D.M.K.), Tufts Medical Center/Tufts University School of Medicine, Boston, MA; the University of Duisburg-Essen (C.W.), Germany; Hôpital Sainte-Anne (J.L.-M.), Paris-Descartes University, France; the Department of Neurology (J.S.), Hospital Universitari Doctor Josep Trueta Institut d'Investigació Biomèdica de Girona, Spain; the Department of Public Health and Primary Care (E.D.A.), Cambridge University, UK; the Department of Cardiology (F.P.), Sapienza University of Rome, Italy; the Departments of Cardiology (S.H.) and Neurology and Epidemiology (M.S.V.E.) and the Division of Cardiology (M.R.D.T.), Columbia University, New York; Inselspital (H.P.M., M.-L.M.), University of Bern; the Division of Neurology (K.N.), Triemli Municipal Hospital, Zurich, Switzerland; the University of Toronto (C.J.), Canada; and Centre Hospitalier Universitaire Vaudois (P.M.), Switzerland.
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Krassen Nedeltchev
From the Department of Neurology (D.E.T., D.M.K.) and the Predictive Analytics and Comparative Effectiveness Center, Institute for Clinical Research and Health Policy Studies (R.R., J.S.L., J.G., D.M.K.), Tufts Medical Center/Tufts University School of Medicine, Boston, MA; the University of Duisburg-Essen (C.W.), Germany; Hôpital Sainte-Anne (J.L.-M.), Paris-Descartes University, France; the Department of Neurology (J.S.), Hospital Universitari Doctor Josep Trueta Institut d'Investigació Biomèdica de Girona, Spain; the Department of Public Health and Primary Care (E.D.A.), Cambridge University, UK; the Department of Cardiology (F.P.), Sapienza University of Rome, Italy; the Departments of Cardiology (S.H.) and Neurology and Epidemiology (M.S.V.E.) and the Division of Cardiology (M.R.D.T.), Columbia University, New York; Inselspital (H.P.M., M.-L.M.), University of Bern; the Division of Neurology (K.N.), Triemli Municipal Hospital, Zurich, Switzerland; the University of Toronto (C.J.), Canada; and Centre Hospitalier Universitaire Vaudois (P.M.), Switzerland.
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Marie-Luise Mono
From the Department of Neurology (D.E.T., D.M.K.) and the Predictive Analytics and Comparative Effectiveness Center, Institute for Clinical Research and Health Policy Studies (R.R., J.S.L., J.G., D.M.K.), Tufts Medical Center/Tufts University School of Medicine, Boston, MA; the University of Duisburg-Essen (C.W.), Germany; Hôpital Sainte-Anne (J.L.-M.), Paris-Descartes University, France; the Department of Neurology (J.S.), Hospital Universitari Doctor Josep Trueta Institut d'Investigació Biomèdica de Girona, Spain; the Department of Public Health and Primary Care (E.D.A.), Cambridge University, UK; the Department of Cardiology (F.P.), Sapienza University of Rome, Italy; the Departments of Cardiology (S.H.) and Neurology and Epidemiology (M.S.V.E.) and the Division of Cardiology (M.R.D.T.), Columbia University, New York; Inselspital (H.P.M., M.-L.M.), University of Bern; the Division of Neurology (K.N.), Triemli Municipal Hospital, Zurich, Switzerland; the University of Toronto (C.J.), Canada; and Centre Hospitalier Universitaire Vaudois (P.M.), Switzerland.
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Cheryl Jaigobin
From the Department of Neurology (D.E.T., D.M.K.) and the Predictive Analytics and Comparative Effectiveness Center, Institute for Clinical Research and Health Policy Studies (R.R., J.S.L., J.G., D.M.K.), Tufts Medical Center/Tufts University School of Medicine, Boston, MA; the University of Duisburg-Essen (C.W.), Germany; Hôpital Sainte-Anne (J.L.-M.), Paris-Descartes University, France; the Department of Neurology (J.S.), Hospital Universitari Doctor Josep Trueta Institut d'Investigació Biomèdica de Girona, Spain; the Department of Public Health and Primary Care (E.D.A.), Cambridge University, UK; the Department of Cardiology (F.P.), Sapienza University of Rome, Italy; the Departments of Cardiology (S.H.) and Neurology and Epidemiology (M.S.V.E.) and the Division of Cardiology (M.R.D.T.), Columbia University, New York; Inselspital (H.P.M., M.-L.M.), University of Bern; the Division of Neurology (K.N.), Triemli Municipal Hospital, Zurich, Switzerland; the University of Toronto (C.J.), Canada; and Centre Hospitalier Universitaire Vaudois (P.M.), Switzerland.
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Patrik Michel
From the Department of Neurology (D.E.T., D.M.K.) and the Predictive Analytics and Comparative Effectiveness Center, Institute for Clinical Research and Health Policy Studies (R.R., J.S.L., J.G., D.M.K.), Tufts Medical Center/Tufts University School of Medicine, Boston, MA; the University of Duisburg-Essen (C.W.), Germany; Hôpital Sainte-Anne (J.L.-M.), Paris-Descartes University, France; the Department of Neurology (J.S.), Hospital Universitari Doctor Josep Trueta Institut d'Investigació Biomèdica de Girona, Spain; the Department of Public Health and Primary Care (E.D.A.), Cambridge University, UK; the Department of Cardiology (F.P.), Sapienza University of Rome, Italy; the Departments of Cardiology (S.H.) and Neurology and Epidemiology (M.S.V.E.) and the Division of Cardiology (M.R.D.T.), Columbia University, New York; Inselspital (H.P.M., M.-L.M.), University of Bern; the Division of Neurology (K.N.), Triemli Municipal Hospital, Zurich, Switzerland; the University of Toronto (C.J.), Canada; and Centre Hospitalier Universitaire Vaudois (P.M.), Switzerland.
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Mitchell S.V. Elkind
From the Department of Neurology (D.E.T., D.M.K.) and the Predictive Analytics and Comparative Effectiveness Center, Institute for Clinical Research and Health Policy Studies (R.R., J.S.L., J.G., D.M.K.), Tufts Medical Center/Tufts University School of Medicine, Boston, MA; the University of Duisburg-Essen (C.W.), Germany; Hôpital Sainte-Anne (J.L.-M.), Paris-Descartes University, France; the Department of Neurology (J.S.), Hospital Universitari Doctor Josep Trueta Institut d'Investigació Biomèdica de Girona, Spain; the Department of Public Health and Primary Care (E.D.A.), Cambridge University, UK; the Department of Cardiology (F.P.), Sapienza University of Rome, Italy; the Departments of Cardiology (S.H.) and Neurology and Epidemiology (M.S.V.E.) and the Division of Cardiology (M.R.D.T.), Columbia University, New York; Inselspital (H.P.M., M.-L.M.), University of Bern; the Division of Neurology (K.N.), Triemli Municipal Hospital, Zurich, Switzerland; the University of Toronto (C.J.), Canada; and Centre Hospitalier Universitaire Vaudois (P.M.), Switzerland.
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Marco R. Di Tullio
From the Department of Neurology (D.E.T., D.M.K.) and the Predictive Analytics and Comparative Effectiveness Center, Institute for Clinical Research and Health Policy Studies (R.R., J.S.L., J.G., D.M.K.), Tufts Medical Center/Tufts University School of Medicine, Boston, MA; the University of Duisburg-Essen (C.W.), Germany; Hôpital Sainte-Anne (J.L.-M.), Paris-Descartes University, France; the Department of Neurology (J.S.), Hospital Universitari Doctor Josep Trueta Institut d'Investigació Biomèdica de Girona, Spain; the Department of Public Health and Primary Care (E.D.A.), Cambridge University, UK; the Department of Cardiology (F.P.), Sapienza University of Rome, Italy; the Departments of Cardiology (S.H.) and Neurology and Epidemiology (M.S.V.E.) and the Division of Cardiology (M.R.D.T.), Columbia University, New York; Inselspital (H.P.M., M.-L.M.), University of Bern; the Division of Neurology (K.N.), Triemli Municipal Hospital, Zurich, Switzerland; the University of Toronto (C.J.), Canada; and Centre Hospitalier Universitaire Vaudois (P.M.), Switzerland.
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Jennifer S. Lutz
From the Department of Neurology (D.E.T., D.M.K.) and the Predictive Analytics and Comparative Effectiveness Center, Institute for Clinical Research and Health Policy Studies (R.R., J.S.L., J.G., D.M.K.), Tufts Medical Center/Tufts University School of Medicine, Boston, MA; the University of Duisburg-Essen (C.W.), Germany; Hôpital Sainte-Anne (J.L.-M.), Paris-Descartes University, France; the Department of Neurology (J.S.), Hospital Universitari Doctor Josep Trueta Institut d'Investigació Biomèdica de Girona, Spain; the Department of Public Health and Primary Care (E.D.A.), Cambridge University, UK; the Department of Cardiology (F.P.), Sapienza University of Rome, Italy; the Departments of Cardiology (S.H.) and Neurology and Epidemiology (M.S.V.E.) and the Division of Cardiology (M.R.D.T.), Columbia University, New York; Inselspital (H.P.M., M.-L.M.), University of Bern; the Division of Neurology (K.N.), Triemli Municipal Hospital, Zurich, Switzerland; the University of Toronto (C.J.), Canada; and Centre Hospitalier Universitaire Vaudois (P.M.), Switzerland.
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John Griffith
From the Department of Neurology (D.E.T., D.M.K.) and the Predictive Analytics and Comparative Effectiveness Center, Institute for Clinical Research and Health Policy Studies (R.R., J.S.L., J.G., D.M.K.), Tufts Medical Center/Tufts University School of Medicine, Boston, MA; the University of Duisburg-Essen (C.W.), Germany; Hôpital Sainte-Anne (J.L.-M.), Paris-Descartes University, France; the Department of Neurology (J.S.), Hospital Universitari Doctor Josep Trueta Institut d'Investigació Biomèdica de Girona, Spain; the Department of Public Health and Primary Care (E.D.A.), Cambridge University, UK; the Department of Cardiology (F.P.), Sapienza University of Rome, Italy; the Departments of Cardiology (S.H.) and Neurology and Epidemiology (M.S.V.E.) and the Division of Cardiology (M.R.D.T.), Columbia University, New York; Inselspital (H.P.M., M.-L.M.), University of Bern; the Division of Neurology (K.N.), Triemli Municipal Hospital, Zurich, Switzerland; the University of Toronto (C.J.), Canada; and Centre Hospitalier Universitaire Vaudois (P.M.), Switzerland.
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David M. Kent
From the Department of Neurology (D.E.T., D.M.K.) and the Predictive Analytics and Comparative Effectiveness Center, Institute for Clinical Research and Health Policy Studies (R.R., J.S.L., J.G., D.M.K.), Tufts Medical Center/Tufts University School of Medicine, Boston, MA; the University of Duisburg-Essen (C.W.), Germany; Hôpital Sainte-Anne (J.L.-M.), Paris-Descartes University, France; the Department of Neurology (J.S.), Hospital Universitari Doctor Josep Trueta Institut d'Investigació Biomèdica de Girona, Spain; the Department of Public Health and Primary Care (E.D.A.), Cambridge University, UK; the Department of Cardiology (F.P.), Sapienza University of Rome, Italy; the Departments of Cardiology (S.H.) and Neurology and Epidemiology (M.S.V.E.) and the Division of Cardiology (M.R.D.T.), Columbia University, New York; Inselspital (H.P.M., M.-L.M.), University of Bern; the Division of Neurology (K.N.), Triemli Municipal Hospital, Zurich, Switzerland; the University of Toronto (C.J.), Canada; and Centre Hospitalier Universitaire Vaudois (P.M.), Switzerland.
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Citation
Recurrent stroke predictors differ in medically treated patients with pathogenic vs other PFOs
David E. Thaler, Robin Ruthazer, Christian Weimar, Jean-Louis Mas, Joaquín Serena, Emanuele Di Angelantonio, Federica Papetti, Shunichi Homma, Heinrich P. Mattle, Krassen Nedeltchev, Marie-Luise Mono, Cheryl Jaigobin, Patrik Michel, Mitchell S.V. Elkind, Marco R. Di Tullio, Jennifer S. Lutz, John Griffith, David M. Kent
Neurology Jul 2014, 83 (3) 221-226; DOI: 10.1212/WNL.0000000000000589

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Abstract

Objective: To examine predictors of stroke recurrence in patients with a high vs a low likelihood of having an incidental patent foramen ovale (PFO) as defined by the Risk of Paradoxical Embolism (RoPE) score.

Methods: Patients in the RoPE database with cryptogenic stroke (CS) and PFO were classified as having a probable PFO-related stroke (RoPE score of >6, n = 647) and others (RoPE score of ≤6 points, n = 677). We tested 15 clinical, 5 radiologic, and 3 echocardiographic variables for associations with stroke recurrence using Cox survival models with component database as a stratification factor. An interaction with RoPE score was checked for the variables that were significant.

Results: Follow-up was available for 92%, 79%, and 57% at 1, 2, and 3 years. Overall, a higher recurrence risk was associated with an index TIA. For all other predictors, effects were significantly different in the 2 RoPE score categories. For the low RoPE score group, but not the high RoPE score group, older age and antiplatelet (vs warfarin) treatment predicted recurrence. Conversely, echocardiographic features (septal hypermobility and a small shunt) and a prior (clinical) stroke/TIA were significant predictors in the high but not low RoPE score group.

Conclusion: Predictors of recurrence differ when PFO relatedness is classified by the RoPE score, suggesting that patients with CS and PFO form a heterogeneous group with different stroke mechanisms. Echocardiographic features were only associated with recurrence in the high RoPE score group.

GLOSSARY

CS=
cryptogenic stroke;
HR=
hazard ratio;
PFO=
patent foramen ovale;
PH=
proportional hazard;
RoPE=
Risk of Paradoxical Embolism;
TEE=
transesophageal echocardiography

Footnotes

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Editorial, page 204

  • Supplemental data at Neurology.org

  • Received August 20, 2013.
  • Accepted in final form February 13, 2014.
  • © 2014 American Academy of Neurology
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