PFO Closure, Oral Anticoagulants or Antiplatelet Therapy After PFO-associated Stroke in Patients Aged 60 to 80 Years (CLOSE-2)

May 20, 2022 updated by: Assistance Publique - Hôpitaux de Paris

Transcatheter Patent Foramen Ovale (PFO) Closure, Oral Anticoagulants or Antiplatelet Therapy After PFO-associated Stroke in Patients Between 60 and 80 Years Old : a Randomised Controlled Trial.

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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Anticipated)

792

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • France
      • Amiens, France, 80054
        • CHU Amiens
        • Contact:
          • Sandrine Canaple, MD
      • Arras, France, 62022
        • CH Arras
        • Contact:
          • Patrick Le-Coz, MD
      • Besançon, France, 25000
        • CHU Jean Minjoz
        • Contact:
          • Fabrice Vuillier, MD
      • Bordeaux, France, 33000
        • CHU Bordeaux - GH Pellegrin
        • Contact:
          • Pauline Renou, MD
      • Brest, France, 29200
        • CHRU La Cavale Blanche
        • Contact:
          • Serge Timsit, MD
      • Bron, France, 69677
        • HCL-Groupement Hospitalier Lyon Est
      • Caen, France, 14000
        • CHU Côte de Nacre
        • Contact:
          • Emmanuel Touzé, MD
      • Créteil, France, 94010
        • Hôpital Henri Mondor
        • Contact:
          • Hassan Hosseini, MD
      • Dijon, France, 21079
        • CHU Dijon-Hôpital François Mitterrand
        • Contact:
          • Yannick Béjot, MD
      • Grenoble, France, 38043
        • CH Grenoble-Site Nord
        • Contact:
          • Isabelle Favre Wiki, MD
      • Le Chesnay, France, 78150
        • CH Versailles-Hôpital Mignot
        • Contact:
          • Fernando Pico, MD
      • Le Kremlin-Bicetre, France, 94370
        • CHU Bicêtre
        • Contact:
          • Christian Denier, MD
      • Lille, France, 59037
        • CHRU Lille-Hôpital Salengro
        • Contact:
          • Nelly Dequatre, MD
      • Marseille, France, 13005
        • Hôpital De La Timone
      • Montpellier, France, 34295
        • Hopital Gui de Chauliac
      • Nancy, France, 54035
        • CHRU Nancy-Hôpital central
        • Contact:
          • Sébastien Richard, MD
      • Nîmes, France, 30900
        • CHU Caremeau
        • Contact:
          • Anne Wacongne, MD
      • Paris, France, 75018
        • APHP Hôpital Bichat
      • Paris, France, 75019
        • Fondation Adolphe de Rothschild
        • Contact:
          • Michaël Obadia, MD
      • Paris, France, 75013
        • Hôpital Pitié Salpêtrière
        • Contact:
          • Sonia Alamowitch, MD
      • Paris, France, 75014
        • Groupe Hospitalier Paris Saint-Joseph
        • Contact:
          • Mathieu Zuber, MD
      • Paris, France, 75010
        • APHP Hôpital Lariboisière
        • Contact:
          • Peggy Reiner, MD
      • Paris, France, 75014
        • GHU Paris Psychiatrie et Neurosciences
        • Contact:
          • Guillaume Turc, MD
      • Perpignan, France, 66000
        • CH Perpignan
      • Poitiers, France, 86021
        • CHU La Miletrie
        • Contact:
          • Jean-Philippe Neau, MD
      • Rouen, France, 76000
        • CHU Rouen-Hôpital Charles-Nicolle
        • Contact:
          • Evelyne Guegan-Massardier, MD
      • Saint Brieuc, France, 22000
        • CH Yves Le Foll
        • Contact:
          • Grégory Couvreur, MD
      • Saint Herblain, France, 44093
        • Chu Nantes-Hopital Nord Laennec
        • Contact:
          • Benoit guillon, MD
      • Saint-Priest en Jarez, France, 42270
        • CHU Saint-Etienne-Hôpital Nord
      • Strasbourg, France, 67000
        • Hôpital Hautepierre
        • Contact:
          • Wolff Wolff, MD
      • Toulouse, France, 31059
        • CHU Toulouse-Hôpital Pierre Paul Riquet
        • Contact:
          • Nicolas Rasposo, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

60 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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:

    • PFO with large shunt (> 20 microbubbles appearing inthe left atrium within 3 cardiac cycles after opacification of the right atrium) detected spontaneously or during provocative maneuvers,
    • PFO with ASA on transesophageal echocardiography (TOE): base of aneurysm >= 15mm and excursion >10 mm.
  • Affiliation to a French Health Insurance system. Informed consent.

Exclusion Criteria:

  • Life expectancy < 4 years.
  • Contraindication to both experimental treatments (PFO closure, oral anticoagulant therapy) or to the reference treatment (antiplatelet therapy) (see paragraph 19.5). Indication to long-term anticoagulant therapy.
  • mRS >= 3.
  • Presence of other medical conditions that would lead to inability to complete the study or interfere with the assessment of outcomes.
  • Previous surgical or transcatheter treatment of PFO or ASA. Expected impossible follow-up or poor compliance.
  • Patient unable to understand the informed consent form. Patient under tutorship, curatorship, or legal protection.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Antiplatelet therapy
Aspirin OR clopidogrel
Drug: Antiplatelet therapy
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
Experimental: Oral anticoagulants, Direct-Acting
Apixaban (5mg twice a day) OR Dabigatran (150 mg twice a day) OR Rivaroxaban (20 mg once a day)
Drug: Oral Anticoagulant, Direct-Acting
Apixaban (5mg twice a day) OR Dabigatran (150 mg twice a day) OR Rivaroxaban (20 mg once a day)
Experimental: PFO closure
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
Drug: Antiplatelet therapy
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
Procedure: Transcatheter PFO closure
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.
Other Names:
  • •Each device for PFO closure must have the CE mark
  • •and be approved by the Interventional Cardiology Committee

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to recurrent stroke (ischemic or hemorrhagic fatal or non-fatal)
Time Frame: 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)

Stroke: sudden onset of focal neurological symptoms related to a disturbance of the cerebral circulation.

Ischemic stroke : at least one of the following criteria:

  • Sudden onset of focal neurological symptoms with the presence of cerebral infarction in the appropriate territory on brain imaging (CT or MRI), regardless of the duration of symptoms (less than or more than 24 hours).
  • Sudden onset of focal neurological symptoms lasting more than 24 hours, with no apparent cause other than cerebral ischemia.

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)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to disabling stroke
Time Frame: 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)
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)
Time to ischemic stroke
Time Frame: 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)

At least one of the following criteria:

  • Sudden onset of focal neurological symptoms with the presence of cerebral infarction in the appropriate territory on brain imaging (CT or MRI), regardless of the duration of symptoms (less than or more than 24 hours).
  • Sudden onset of focal neurological symptoms lasting more than 24 hours, with no apparent cause other than cerebral ischemia.
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
Time Frame: 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)
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,
Time Frame: 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)
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
Time Frame: 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)
  • death related to a cardiac or vascular cause.
  • death due to hemorrhage.
  • death due to pulmonary embolism.
  • sudden death: death occurring in less than 24 hours, unexpectedly in a subject in apparent good health and whose condition was stable or was improving.
  • death with no documented non-vascular cause.
  • fatal stroke: death occurring within 30 days of a stroke (ischemic or hemorrhagic).
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
Time Frame: 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)
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
Time Frame: 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)]
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
Time Frame: 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)

Life-threatening

  • Fatal hemorrhage.
  • Drop in hemoglobin by ≥ 5 g/dL (or drop in hematocrit by 15% or more in absolute value)
  • Symptomatic intracranial hemorrhage (confirmed by appropriate investigations, classified as cerebral hemorrhage, subarachnoid hemorrhage and subdural hematoma).
  • Transfusion ≥ 4 units of packed cells (or equivalent of whole blood)*.

Major

  • Transfusion ≤ 3 units of packed cells (or equivalent of whole blood)*.
  • Requiring hospitalization (or prolonging hospitalization).
  • Requiring surgical treatment.
  • Intraocular hemorrhage with significant loss of vision.
  • Other hemorrhage responsible for significant disability according to the investigator.
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,
Time Frame: 6 months after PFO closure
  • Success of device implantation: deployment of the device in the appropriate place and removal of the placement system.
  • Success of the procedure: successful implantation with no complications before the patient's discharge.
  • Success of PFO closure: success of the procedure with no residual shunt or minimal residual shunt on echocardiography performed 6 months after the procedure.
6 months after PFO closure
Time to ischemic stroke recurrence according to the presence of a residual shunt
Time Frame: 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]
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
Time Frame: 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)]
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
Time Frame: Within 4 weeks following the procedure (PFO closure)

Life-threatening

  • Cardiac perforation with tamponade requiring emergency drainage.
  • Cerebral air embolism responsible for acute neurological disorders
  • Embolization of the device.
  • Life-threatening hematoma at the puncture site or retroperitoneal.
  • Complications of general anesthesia or TOE requiring intensive care and/or surgical operation.

Major

  • Hemorrhage at the puncture site or retroperitoneal requiring transfusion or surgery.
  • Arteriovenous fistula, pseudoaneurysm requiring surgery.
  • Peripheral nerve lesion with disabling neurological deficit persisting > 1 month.
  • Cardiac arrhythmias (particularly AF) during catheterization or post-procedure requiring treatment >= 1 month.
  • Infective endocarditis.
  • Asymptomatic late thrombosis of the device.
  • Any device-related complication requiring surgery.
  • Any other complication related to the transcatheter treatment or anesthesia, considered to be major by the investigator.
Within 4 weeks following the procedure (PFO closure)
Costs
Time Frame: Within 48 months after randomization
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)
Time Frame: Within 48 months after randomization

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assistance Publique - Hôpitaux de Paris

Collaborators

Ministry of Health, France
W.L.Gore & Associates
Abbott
Centre Hospitalier St Anne
Occlutech International AB

Investigators

  • Principal Investigator: Jean-Louis Mas, MD, GHU Psychiatrie et Neurosciences Paris
  • Study Director: Gilles Chatellier, MD, Hopital Europeen Georges-Pompidou

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

June 1, 2022

Primary Completion (Anticipated)

June 1, 2030

Study Completion (Anticipated)

June 1, 2030

Study Registration Dates

First Submitted

May 4, 2022

First Submitted That Met QC Criteria

May 20, 2022

First Posted (Actual)

May 24, 2022

Study Record Updates

Last Update Posted (Actual)

May 24, 2022

Last Update Submitted That Met QC Criteria

May 20, 2022

Last Verified

May 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • APHP211041
  • 2021-A03197-34 (Other Identifier: IDRCB)
  • PHRC-20-0680 (Other Identifier: Ministry of health (France))

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Individual participant data (IPD) that underlie results in publication could be shared. IPD detailed in the protocol of a planned metaanalysis could be shared

IPD Sharing Time Frame

Two years after the last publication

IPD Sharing Access Criteria

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).

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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