Jean-Louis Mas1, Geneviève Derumeaux1, Benoît Guillon1, Evelyne Massardier1, Hassan Hosseini1, Laura Mechtouff1, Caroline Arquizan1, Yannick Béjot1, Fabrice Vuillier1, Olivier Detante1, Céline Guidoux1, Sandrine Canaple1, Claudia Vaduva1, Nelly Dequatre-Ponchelle1, Igor Sibon1, Pierre Garnier1, Anna Ferrier1, Serge Timsit1, Emmanuelle Robinet-Borgomano1, Denis Sablot1, Jean-Christophe Lacour1, Mathieu Zuber1, Pascal Favrole1, Jean-François Pinel1, Marion Apoil1, Peggy Reiner1, Catherine Lefebvre1, Patrice Guérin1, Christophe Piot1, Roland Rossi1, Jean-Luc Dubois-Randé1, Jean-Christophe Eicher1, Nicolas Meneveau1, Jean-René Lusson1, Bernard Bertrand1, Jean-Marc Schleich1, François Godart1, Jean-Benoit Thambo1, Laurent Leborgne1, Patrik Michel1, Luc Pierard1, Guillaume Turc1, Martine Barthelet1, Anaïs Charles-Nelson1, Christian Weimar1, Thierry Moulin1, Jean-Michel Juliard1, Gilles Chatellier1. 1. From the Department of Neurology, Sainte-Anne Hospital, INSERM 894, Département Hospitalo-Universitaire (DHU) NeuroVasc Sorbonne Paris-Cité (J.-L.M., G.T.), and the Department of Neurology, Saint-Joseph Hospital (M.Z.), Paris Descartes University, the Department of Neurology and Stroke Unit (C.G.) and the Department of Cardiology (J.-M.J.), Bichat Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), INSERM 1148, DHU FIRE (Fibrosis Inflammation and Remodeling in Cardiovascular, Renal, and Respiratory Diseases) Sorbonne Paris-Cité, the Department of Neurology, Saint-Antoine Hospital, AP-HP, Pierre et Marie Curie University (P.F.), the Department of Neurology, Lariboisière Hospital, DHU NeuroVasc Sorbonne Paris-Cité, Paris Diderot University (P.R.), and the Epidemiology and Clinical Research Unit, Georges Pompidou European Hospital, AP-HP, INSERM Centre d'Investigation Clinique 1418 (A.C.-N., G.C.), Paris, the Departments of Physiology (G.D.), Neurology (H.H.), and Cardiology (J.-L.D.-R.), Henri Mondor Hospital, AP-HP, University Paris Est Creteil, Creteil, the Departments of Neurology (B.G.) and Cardiology (P. Guérin), Centre Hospitalier Universitaire (CHU) Nantes, Nantes, the Department of Neurology, University Hospital, Rouen (E.M.), the Stroke Department (L.M.) and the Departments of Interventional Cardiology (R.R.) and Cardiovascular Investigations (M.B.), Pierre Wertheimer and Louis Pradel Hospitals, Lyon University, Lyon, the Department of Neurology, Gui de Chauliac Hospital, INSERM 894 (C.A.), and the Department of Interventional Cardiology, Clinique du Millénaire, INSERM 1191 (C.P.), Montpellier University, Montpellier, the Department of Neurology, Dijon Stroke Registry, EA 7460 (Y.B.), and the Department of Cardiology (J.-C.E.), University Hospital, Burgundy University, Dijon, the Departments of Neurology (F.V., T.M.) and Cardiology (N.M.), Jean Minjoz University Hospital, Franche-Comté University, Besançon, the Departments of Neurology (O.D.) and Cardiology (B.B.), Michallon Hospital, Grenoble Alpes University, Grenoble, the Department of Neurology and Stroke Unit (S.C.) and the Department of Cardiology (L.L.), University Hospital, Jules Verne Picardie University, Amiens, the Department of Neurology, Yves le Foll Hospital, Saint Brieuc (C.V.), the Department of Neurology and Stroke Unit (N.D.-P.) and the Department of Cardiology and Congenital Heart Disease (F.G.), Centre Hospitalier Régional Universitaire (CHRU) Lille, Lille Nord de France University, Lille, the Department of Neurology and Stroke Unit (I.S.) and the Department of Congenital Cardiac Diseases (J.-B.T.), CHU Bordeaux, Bordeaux University, Bordeaux, the Department of Neurology, University Hospital, INSERM 1059, Lyon University, Saint-Etienne (P. Garnier), the Departments of Neurology (A.F.) and Cardiology (J.-R.L.), University Hospital, Clermont-Ferrand, the Department of Neurology and Stroke Unit, Cavale Blanche Hospital, INSERM 1078, University of Western Brittany, Brest (S.T.), the Department of Neurology, La Timone Hospital, Aix-Marseille University, Marseille (E.R.-B.), the Department of Neurology, Saint-Jean Hospital, Perpignan (D.S.), the Department of Neurology and Stroke Unit, Central Hospital, Nancy (J.-C.L.), the Departments of Neurology (J.-F.P.) and Cardiology and Vascular Diseases (J.-M.S.), Pontchaillou Hospital, Rennes University, Rennes, the Department of Neurology, Caen University Hospital, Caen (M.A.), the Department of Neurology, Docteur Schaffner Hospital, Lens (C.L.) - all in France; the Stroke Center, Department of Neurology, Vaudois University Hospital, Lausanne University, Lausanne, Switzerland (P.M.); the Department of Cardiology, CHU Sart Tilman, Liege University, Liege, Belgium (L.P.); and the Department of Neurology, University Hospital, Duisburg-Essen University, Duisberg-Essen, Germany (C.W.).
Abstract
BACKGROUND: Trials of patent foramen ovale (PFO) closure to prevent recurrent stroke have been inconclusive. We investigated whether patients with cryptogenic stroke and echocardiographic features representing risk of stroke would benefit from PFO closure or anticoagulation, as compared with antiplatelet therapy. METHODS: In a multicenter, randomized, open-label trial, we assigned, in a 1:1:1 ratio, patients 16 to 60 years of age who had had a recent stroke attributed to PFO, with an associated atrial septal aneurysm or large interatrial shunt, to transcatheter PFO closure plus long-term antiplatelet therapy (PFO closure group), antiplatelet therapy alone (antiplatelet-only group), or oral anticoagulation (anticoagulation group) (randomization group 1). Patients with contraindications to anticoagulants or to PFO closure were randomly assigned to the alternative noncontraindicated treatment or to antiplatelet therapy (randomization groups 2 and 3). The primary outcome was occurrence of stroke. The comparison of PFO closure plus antiplatelet therapy with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 2, and the comparison of oral anticoagulation with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 3. RESULTS: A total of 663 patients underwent randomization and were followed for a mean (±SD) of 5.3±2.0 years. In the analysis of randomization groups 1 and 2, no stroke occurred among the 238 patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the antiplatelet-only group (hazard ratio, 0.03; 95% confidence interval, 0 to 0.26; P<0.001). Procedural complications from PFO closure occurred in 14 patients (5.9%). The rate of atrial fibrillation was higher in the PFO closure group than in the antiplatelet-only group (4.6% vs. 0.9%, P=0.02). The number of serious adverse events did not differ significantly between the treatment groups (P=0.56). In the analysis of randomization groups 1 and 3, stroke occurred in 3 of 187 patients assigned to oral anticoagulants and in 7 of 174 patients assigned to antiplatelet therapy alone. CONCLUSIONS: Among patients who had had a recent cryptogenic stroke attributed to PFO with an associated atrial septal aneurysm or large interatrial shunt, the rate of stroke recurrence was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone. PFO closure was associated with an increased risk of atrial fibrillation. (Funded by the French Ministry of Health; CLOSE ClinicalTrials.gov number, NCT00562289 .).
RCT Entities:
BACKGROUND: Trials of patent foramen ovale (PFO) closure to prevent recurrent stroke have been inconclusive. We investigated whether patients with cryptogenic stroke and echocardiographic features representing risk of stroke would benefit from PFO closure or anticoagulation, as compared with antiplatelet therapy. METHODS: In a multicenter, randomized, open-label trial, we assigned, in a 1:1:1 ratio, patients 16 to 60 years of age who had had a recent stroke attributed to PFO, with an associated atrial septal aneurysm or large interatrial shunt, to transcatheter PFO closure plus long-term antiplatelet therapy (PFO closure group), antiplatelet therapy alone (antiplatelet-only group), or oral anticoagulation (anticoagulation group) (randomization group 1). Patients with contraindications to anticoagulants or to PFO closure were randomly assigned to the alternative noncontraindicated treatment or to antiplatelet therapy (randomization groups 2 and 3). The primary outcome was occurrence of stroke. The comparison of PFO closure plus antiplatelet therapy with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 2, and the comparison of oral anticoagulation with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 3. RESULTS: A total of 663 patients underwent randomization and were followed for a mean (±SD) of 5.3±2.0 years. In the analysis of randomization groups 1 and 2, no stroke occurred among the 238 patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the antiplatelet-only group (hazard ratio, 0.03; 95% confidence interval, 0 to 0.26; P<0.001). Procedural complications from PFO closure occurred in 14 patients (5.9%). The rate of atrial fibrillation was higher in the PFO closure group than in the antiplatelet-only group (4.6% vs. 0.9%, P=0.02). The number of serious adverse events did not differ significantly between the treatment groups (P=0.56). In the analysis of randomization groups 1 and 3, stroke occurred in 3 of 187 patients assigned to oral anticoagulants and in 7 of 174 patients assigned to antiplatelet therapy alone. CONCLUSIONS: Among patients who had had a recent cryptogenic stroke attributed to PFO with an associated atrial septal aneurysm or large interatrial shunt, the rate of stroke recurrence was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone. PFO closure was associated with an increased risk of atrial fibrillation. (Funded by the French Ministry of Health; CLOSE ClinicalTrials.gov number, NCT00562289 .).
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