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| ID | Type | Description | Link |
|---|---|---|---|
| 2021-A03197-34 | Other Identifier | IDRCB | |
| PHRC-20-0680 | Other Identifier | Ministry of health (France) |
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| Name | Class |
|---|---|
| Ministry of Health, France | OTHER_GOV |
| W.L.Gore & Associates | INDUSTRY |
| Abbott | INDUSTRY |
| Occlutech International AB |
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To assess whether PFO closure plus antiplatelet therapy is superior to antiplatelet therapy alone and whether oral anticoagulant therapy is superior to antiplatelet therapy to prevent stroke recurrence in patients aged 60 to 80 years with a PFO with large shunt (> 20 microbubbles) or a PFO associated with an ASA (> 10 mm), and an otherwise unexplained ischemic stroke.
The CLOSE trial (NCT00562289, NEJM 2017) has unambiguously demonstrated the superiority of patent foramen ovale (PFO) closure over antiplatelet therapy alone in patients aged up to 60 years with a PFO associated with an atrial septal aneurysm (ASA) or a large right-to-left shunt (so-called "high-risk PFO"), and an otherwise unexplained ischemic stroke. Oral anticoagulant therapy is also a logical approach assuming that PFO-related strokes are due to paradoxical embolism which implies a venous source of embolism, or to direct embolization of a thrombus formed at the atrial level. The CLOSE trial also suggested that oral anticoagulants might reduce stroke recurrence compared to aspirin.
There is accumulating evidence that presence of a PFO is significantly associated with cryptogenic stroke in patients over 60 years. Cryptogenic ischemic strokes represent about one third of all ischemic strokes in patients older than 60 years. However, the optimal therapeutic strategy in patients older than 60 years with a PFO and an otherwise unexplained ischemic stroke is unknown, because these patients were excluded from randomized trials.
The hypothesis tested in this trial is that transcatheter PFO closure plus long-term antiplatelet therapy is superior to antiplatelet therapy alone and that oral anticoagulant therapy is superior to antiplatelet therapy to prevent recurrent stroke in patients aged 60 to 80 years who have a high-risk PFO and a recent otherwise unexplained ischemic stroke.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Antiplatelet therapy | Active Comparator | Aspirin OR clopidogrel |
|
| Oral anticoagulants, Direct-Acting | Experimental | Apixaban (5mg twice a day) OR Dabigatran (150 mg twice a day) OR Rivaroxaban (20 mg once a day) |
|
| PFO closure | Experimental | PFO closure followed by dual antiplatelet therapy (aspirin 75 mg/d + clopidogrel 75 mg/d) for 3 months, then by single antiplatelet therapy by aspirin or clopidogrel |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Transcatheter PFO closure | Procedure | PFO closure followed by dual antiplatelet therapy (aspirin 75 mg/d + clopidogrel 75 mg/d) for 3 months, then by single antiplatelet therapy by aspirin or clopidogrel until the end of the study. |
| Measure | Description | Time Frame |
|---|---|---|
| Time to recurrent stroke (ischemic or hemorrhagic fatal or non-fatal) | Stroke: sudden onset of focal neurological symptoms related to a disturbance of the cerebral circulation. Ischemic stroke : at least one of the following criteria:
Intracerebral hemorrhage: sudden onset of focal neurological symptoms with the presence of cerebral hemorrhage in the appropriate territory on brain imaging (CT or MRI), regardless of the duration of symptoms (less than or more than 24 hours) and regardless of the cause of the hemorrhage (spontaneous or secondary to trauma, tumour or another cause). Unknown type of stroke : the type of stroke cannot be determined with certainty and the symptoms last more than 24 hours. | From date of randomization until the date of first recurrent stroke, assessed from up to 4 years (for the last patient included) to up to 8 years (for the first patient included) |
| Measure | Description | Time Frame |
|---|---|---|
| Time to disabling stroke | mRS score greater than or equal to 3, with an increase of at least 2 points compared to the last mRS score before the stroke. | From date of randomization until the date of first recurrent disabling stroke, assessed from up to 4 years (for the last patient included) to up to 8 years (for the first patient included) |
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Inclusion Criteria:
Man or woman aged 60 to 80 years.
Recent (≤ 6 months) ischemic stroke confirmed by cerebral imaging regardless of symptom duration.
Absence of a more probable cause of stroke than PFO after a standardized etiological work-up (see addenda).
Presence of a PFO with at least 1 of the 2 following characteristics:
Affiliation to a French Health Insurance system. Informed consent.
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Carla Vandenabele | Contact | +331 44 84 57 27 | carla.vandenabele@aphp.fr | |
| Malha Berrah | Contact | malha.berrah@aphp.fr |
| Name | Affiliation | Role |
|---|---|---|
| Jean-Louis Mas, MD | GHU Psychiatrie et Neurosciences Paris | Principal Investigator |
| Gilles Chatellier, MD | Hôpital Européen Georges-Pompidou | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| CHU Amiens | Recruiting | Amiens | 80054 | France |
Individual participant data (IPD) that underlie results in publication could be shared. IPD detailed in the protocol of a planned metaanalysis could be shared
Two years after the last publication
Data sharing must be accepted by the sponsor and the PI based on a scientific project and scientific involvement of the PI team. Collaboration will be fostered.
Data sharing must respect the agreements made with funders.
Teams wishing obtain IPD must meet the sponsor and PI team to present scientific (and commercial) purpose, IPD needed, format of data transmission, and timeframe. Technical feasability and financial support will be discussed before mandatory contractual agreement.
Processing of shared data must comply with European General Data Protection Regulation (GDPR).
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| INDUSTRY |
| Centre Hospitalier St Anne | OTHER |
PFO closure + antiplatelet therapy versus antiplatelet therapy alone Oral anticoagulants versus antiplatelet therapy
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The clinical event adjudication committee will blind to the treatment allocated by randomization.
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| Oral Anticoagulant, Direct-Acting | Drug | Apixaban (5mg twice a day) OR Dabigatran (150 mg twice a day) OR Rivaroxaban (20 mg once a day) |
|
| Antiplatelet therapy | Drug | Patients randomized to this arm will receive antiplatelet therapy throughout the study : aspirin 75 mg/d + clopidogrel 75 mg/d) for 3 months, then single antiplatelet therapy by aspirin or clopidogrel |
|
| Time to ischemic stroke |
At least one of the following criteria:
|
| From date of randomization until the date of first recurrent ischemic stroke, assessed from up to 4 years (for the last patient included) to up to 8 years (for the first patient included) |
| Time to ischemic stroke or systemic embolism | Clinical features related to embolism usually affecting a limb, mesenteric, splenic, or renal artery. The diagnosis of embolism must be confirmed by appropriate investigations. | From date of randomization until the date of first recurrent ischemic stroke or systemic embolism, assessed from up to 4 years (for the last patient included) to up to 8 years (for the first patient included) |
| Time to transient ischemic attack, | Sudden onset of neurological symptoms, presumed to be ischemic, resolving in less than 24 hours, clearly attributable to focal involvement of the central nervous system (or of the eye) with no signs of a corresponding recent cerebral infarction on brain imaging. The diagnosis of TIA will be confirmed by a neurologist, considering clinical data and brain imaging (MRI with diffusion sequence is recommended). | From date of randomization until the date of first transient ischemic attack, assessed from up to 4 years (for the last patient included) to up to 8 years (for the first patient included) |
| Time to vascular death |
| From date of randomization until the date of vascular death, assessed from up to 4 years (for the last patient included) to up to 8 years (for the first patient included) |
| Time to all-cause mortality | Vascular (see definition) or nonvascular death: death due to a documented non-vascular cause (infection, cancer, accident, suicide, etc.). | From date of randomization until the date of death, assessed from up to 4 years (for the last patient included) to up to 8 years (for the first patient included) |
| Quality of life score | Measured by using the European Quality Of Life (EQ-5D) auto-questionnaire. The digits for the five dimensions are combined into a 5-digit number that describes the patient's health state. The visual analogue scale (VAS) records the patient's self-rated health on a vertical axis from 0 (worst health) to 100 (best health) | Every 6 months after randomization or up to 4 years (for the last patient included) to up to 8 years (for the first patient included)] |
| Time to fatal, life-threatening or major hemorrhage, including intracerebral and Intracranial hemorrhage | Life-threatening
Major
| From date of randomization until the date of first fatal,life-threatening or major hemorrhage,including intracerebral and Intracranial hemorrhage,assessed from up to 4 years(for the last patient included) to up to 8 years(for the first patient included) |
| Proportion of success of device implantation, of the procedure and of PFO closure, |
| 6 months after PFO closure |
| Time to ischemic stroke recurrence according to the presence of a residual shunt | From control echocardiography after PFO closure to the end of the patient's follow-up | From date of PFO closure until the date of first ischemic stroke recurrence, assessed from up to 4 years (for the last patient included) to up to 8 years (for the first patient included), according to the presence of residual shunt] |
| Time to new-onset atrial fibrillation | Atrial fibrillation lasting at least 30 seconds | From date of randomization until the date of new-onset atrial fibrillation, assessed from up to 4 years (for the last patient included) to up to 8 years (for the first patient included)] |
| Proportion of fatal, life-threatening or major procedure- or device-related complications | Life-threatening
Major
| Within 4 weeks following the procedure (PFO closure) |
| Costs | Costs will be estimated from the viewpoint of the healthcare system (hospital admission, transportation, study interventions, emergency room visit without admission,consultations,imaging) | Within 48 months after randomization |
| Incremental cost-utility ratio at 4 years (ICUR) | The incremental cost-utility ratio (ICUR) will be calculated as difference in costs (between groups)/difference in QALYs (Quality-Adjusted Life Year) between groups. The QALYs will be constructed with the EuroQoL-5D (EQ-5D) questionnaire and value sets | Within 48 months after randomization |
| Centre Hospitalier de la Côte Basque | Recruiting | Bayonne | 64100 | France |
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| CHU Jean Minjoz | Recruiting | Besançon | 25000 | France |
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| CHU Bordeaux - GH Pellegrin | Recruiting | Bordeaux | 33000 | France |
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| CHRU La Cavale Blanche | Recruiting | Brest | 29200 | France |
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| HCL-Groupement Hospitalier Lyon Est | Recruiting | Bron | 69677 | France |
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| CHU Côte de Nacre | Recruiting | Caen | 14000 | France |
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| CHU Clermont Ferrand | Recruiting | Clermont-Ferrand | 63000 | France |
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| CH Sud Francilien | Recruiting | Corbeil-Essonnes | 91100 | France |
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| Hôpital Henri Mondor | Recruiting | Créteil | 94010 | France |
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| CHU Dijon-Hôpital François Mitterrand | Recruiting | Dijon | 21079 | France |
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| Hôpital Raymond Poincaré | Recruiting | Garches | 92380 | France |
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| CH Grenoble-Site Nord | Recruiting | Grenoble | 38043 | France |
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| GPE Hospitalier La Rochelle-Ré-Aunis | Recruiting | La Rochelle | 17000 | France |
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| CH Versailles-Hôpital Mignot | Recruiting | Le Chesnay | 78150 | France |
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| CHU Bicêtre | Recruiting | Le Kremlin-Bicêtre | 94370 | France |
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| CHRU Lille-Hôpital Salengro | Recruiting | Lille | 59037 | France |
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| CHU Limoges - Site Dupuytren | Recruiting | Limoges | 87042 | France |
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| Hôpital de la Timone | Recruiting | Marseille | 13005 | France |
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| Grand Hôpital de l'Est Francilien | Recruiting | Meaux | 77140 | France |
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| Hôpital Gui de Chauliac | Recruiting | Montpellier | 34295 | France |
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| CHU de Nice-Hôpital Pasteur | Recruiting | Nice | 06000 | France |
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| CHU Carémeau | Recruiting | Nîmes | 30900 | France |
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| CH Orsay | Recruiting | Orsay | 91400 | France |
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| APHP Hôpital Lariboisière | Recruiting | Paris | 75010 | France |
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| Hôpital Pitié Salpêtrière | Recruiting | Paris | 75013 | France |
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| GHU Paris Psychiatrie et Neurosciences | Recruiting | Paris | 75014 | France |
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| Groupe Hospitalier Paris Saint-Joseph | Recruiting | Paris | 75014 | France |
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| Fondation Adolphe de Rothschild | Recruiting | Paris | 75019 | France |
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| CH Perpignan | Recruiting | Perpignan | 66000 | France |
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| CHU La Milétrie | Recruiting | Poitiers | 86021 | France |
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| Hôpital Novo | Recruiting | Pontoise | 95300 | France |
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| CHU Rennes-Hôpital Pontchaillou | Recruiting | Rennes | 35000 | France |
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| CHU Rouen-Hôpital Charles-Nicolle | Recruiting | Rouen | 76000 | France |
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| CH Yves Le Foll | Recruiting | Saint-Brieuc | 22000 | France |
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| CHU Nantes-Hôpital Nord Laennec | Recruiting | Saint-Herblain | 44093 | France |
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| CHU Saint-Etienne-Hôpital Nord | Recruiting | Saint-Priest-en-Jarez | 42270 | France |
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| Hôpital Hautepierre | Recruiting | Strasbourg | 67000 | France |
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| Hôpital Foch | Recruiting | Suresnes | 92150 | France |
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| CHU Toulouse-Hôpital Pierre Paul Riquet | Recruiting | Toulouse | 31059 | France |
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| CHRU Tours- Hôpital Bretonneau | Recruiting | Tours | 37000 | France |
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| Centre Hospitalier de Valenciennes | Recruiting | Valenciennes | 59300 | France |
|
| ID | Term |
|---|---|
| D000083242 | Ischemic Stroke |
| D054092 | Foramen Ovale, Patent |
| ID | Term |
|---|---|
| D020521 | Stroke |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D006344 | Heart Septal Defects, Atrial |
| D006343 | Heart Septal Defects |
| D006330 | Heart Defects, Congenital |
| D018376 | Cardiovascular Abnormalities |
| D006331 | Heart Diseases |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
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| ID | Term |
|---|---|
| D065427 | Factor Xa Inhibitors |
| ID | Term |
|---|---|
| D000991 | Antithrombins |
| D015842 | Serine Proteinase Inhibitors |
| D011480 | Protease Inhibitors |
| D004791 | Enzyme Inhibitors |
| D045504 | Molecular Mechanisms of Pharmacological Action |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
| D000925 | Anticoagulants |
| D006401 | Hematologic Agents |
| D045506 | Therapeutic Uses |
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