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Patent Foramen Ovale Closure or Anticoagulants Versus Antiplatelet Therapy to Prevent Stroke Recurrence (CLOSE)

Primary Purpose

Ischemic Stroke, Patent Foramen Ovale, Atrial Septal Aneurysm

Status
Completed
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
aspirin
Antivitamins K or rivaroxaban or dabigatran or apixaban
Devices for PFO closure
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Ischemic Stroke focused on measuring Stroke, Patent Foramen Ovale, Atrial septal aneurysm, Antiplatelet therapy, Oral anticoagulants, Transcatheter closure, Migraine

Eligibility Criteria

16 Years - 60 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Male or female, 16 <= age <= 60 ans.
  • Recent (<= 6 months) ischemic stroke documented by CT-san or MRI (whatever the duration of symptoms: shorter or longer than 24 hours).
  • Modified Rankin score <=3.
  • Absence of any other identifiable cause of stroke

  • Presence of a PFO with at least one of the following characteristics:

    • right-to-left shunt > 30 microbubbles, at rest or during provocative manoeuvres, by TTE ou TOE
    • associated ASA (base ≥ à 15 mm, total excursion > à 10 mm) by TOE
  • Informed consent.

Exclusion Criteria:

  • Any identifiable cause of ischemic stroke other than PFO.
  • Isolated atrial septal defect or atrial septal defect associated with PFO with significant left-to-right shunt requiring closure.
  • Previous surgical or endovascular treatments of PFO or ASA.
  • Known or suspected pregnancy (beta hCG test must be performed before inclusion).
  • Women who are breast-feeding.
  • Inability to comply with the treatments or follow-up requirements of the study.
  • No affiliation to the national health service.
  • Presence of other medical problems that would either lead to inability to complete the trial or interfere with the assessment of outcomes.
  • Participation in another study.
  • Unable to understand the full meaning of the informed consent.

  • Related medical treatments of the trial:

    • Long-term oral anticoagulation or antiplatelet therapy is indicated for another disease.

    • Contra-indication to antiplatelet therapy or oral anticoagulants :

      • 3-arm trial : contra-indication to aspirin or clopidogrel or antivitamins K
      • 2-arm trial (closure vs antiplatelet therapy) : contra-indication to aspirin or clopidogrel
      • 2-arm trial (antivitamins K vs antiplatelet therapy : contra-indication to antivitamins K or to any antiplatelet drug
    • Increased risk of bleeding, such as severe hepatic insufficiency, current peptic ulceration, proliferative diabetic retinopathy, history of severe systemic bleeding (e.g. gastrointestinal bleeding, gross hematuria, intraocular bleeding, hemorrhagic stroke, or intracranial hemorrhage), or other history of bleeding diathesis or coagulopathy.

  • Related to endovascular treatments :

    • Infection requiring antibiotics (inclusion is possible after healing, 4 weeks after withdrawal of antibiotics).
    • Very large or multi-perforated ASA for which endovascular treatments is deemed too risky.
    • Presence of thrombus or occlusion between the venous access and the right atrium.
    • Presence of an inferior vena cava filter.
    • Severe pulmonary hypertension.

Sites / Locations

  • Hôpital Saint-Anne

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Experimental

Experimental

Arm Label

aspirin

anticoagulant

Devices for PFO closure

Arm Description

aspirin use like antiplatelet

Antivitamins K or rivaroxaban or dabigatran or apixaban

Devices for PFO closure

Outcomes

Primary Outcome Measures

stroke(fatal or not)

Secondary Outcome Measures

Disabling stroke
Ischemic stroke
Cerebral haemorrhage
Ischemic stroke, TIA, or systemic embolism
Death (all causes)
Vascular death
Moderate to severe bleeding complications
Procedural or device complications

Full Information

First Posted
November 21, 2007
Last Updated
October 18, 2017
Sponsor
Assistance Publique - Hôpitaux de Paris
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1. Study Identification

Unique Protocol Identification Number
NCT00562289
Brief Title
Patent Foramen Ovale Closure or Anticoagulants Versus Antiplatelet Therapy to Prevent Stroke Recurrence
Acronym
CLOSE
Official Title
Closure of Patent Foramen Ovale or Anticoagulants Versus Antiplatelet Therapy to Prevent Stroke Recurrence
Study Type
Interventional

2. Study Status

Record Verification Date
January 2017
Overall Recruitment Status
Completed
Study Start Date
December 2007 (undefined)
Primary Completion Date
December 2016 (Actual)
Study Completion Date
December 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
A patent foramen ovale (PFO) is found more frequently in patients with an ischemic stroke than in control subjects. Therapeutic options to prevent stroke recurrence include antiplatelet drugs, oral anticoagulants, and transcatheter closure of the foramen. However, there are no published studies showing convincingly the superiority of any one of these strategies in preventing stroke recurrence. The aim of this randomized clinical trial is to assess whether chronic anticoagulation on the one hand and transcatheter on the other hand are superior to chronic antiplatelet therapy in preventing stroke recurrence.
Detailed Description
Secondary prevention for stroke patients with PFO is a subject of considerable debate. Therapeutic options include antiplatelet drugs, oral anticoagulants, and transcatheter closure of the foramen. There are no published studies showing convincingly the superiority of any one of these strategies in preventing stroke recurrence. All the therapeutic options have some risks and unless randomised trials can define who should be treated with what (if anything), and for how long, we could end up exposing patients to unnecessary complications of treatment. The primary objective of this study is to assess whether chronic anticoagulation (INR 2 to 3) on the one hand and endovascular treatment on the other hand are superior to chronic antiplatelet therapy in preventing stroke recurrence in young (16 to 60 years) patients with a PFO (> 30 microbubbles or associated with an atrial septal aneurysm) and an otherwise unexplained ischaemic stroke. Secondary objectives of the study are: to evaluate the safety of the three therapeutic options, in terms of major drug-, device- or procedure-related complications, in order to allow a benefit/risk assessment of each therapeutic option in this population. to assess the rate of technical success and effectiveness of endovascular procedure to treat PFO and ASA.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ischemic Stroke, Patent Foramen Ovale, Atrial Septal Aneurysm, Migraine
Keywords
Stroke, Patent Foramen Ovale, Atrial septal aneurysm, Antiplatelet therapy, Oral anticoagulants, Transcatheter closure, Migraine

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
664 (Actual)

8. Arms, Groups, and Interventions

Arm Title
aspirin
Arm Type
Active Comparator
Arm Description
aspirin use like antiplatelet
Arm Title
anticoagulant
Arm Type
Experimental
Arm Description
Antivitamins K or rivaroxaban or dabigatran or apixaban
Arm Title
Devices for PFO closure
Arm Type
Experimental
Arm Description
Devices for PFO closure
Intervention Type
Drug
Intervention Name(s)
aspirin
Other Intervention Name(s)
clopidogrel, combination aspirin-dipyridamole
Intervention Description
during the follow up
Intervention Type
Drug
Intervention Name(s)
Antivitamins K or rivaroxaban or dabigatran or apixaban
Intervention Description
during the follow up
Intervention Type
Device
Intervention Name(s)
Devices for PFO closure
Other Intervention Name(s)
Each device for PFO closure must have the CE mark, and be approved by the Interventional Cardiology Committee
Intervention Description
endovascular treatment no longer than 21 days after the random.
Primary Outcome Measure Information:
Title
stroke(fatal or not)
Time Frame
during the follow up (between 2 or 9 years)
Secondary Outcome Measure Information:
Title
Disabling stroke
Time Frame
during the follow-up
Title
Ischemic stroke
Time Frame
during the follow-up
Title
Cerebral haemorrhage
Time Frame
during the follow-up
Title
Ischemic stroke, TIA, or systemic embolism
Time Frame
during the follow-up
Title
Death (all causes)
Time Frame
during the follow-up
Title
Vascular death
Time Frame
during the follow-up
Title
Moderate to severe bleeding complications
Time Frame
during the follow-up
Title
Procedural or device complications
Time Frame
within 30 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female, 16 <= age <= 60 ans. Recent (<= 6 months) ischemic stroke documented by CT-san or MRI (whatever the duration of symptoms: shorter or longer than 24 hours). Modified Rankin score <=3. Absence of any other identifiable cause of stroke Presence of a PFO with at least one of the following characteristics: right-to-left shunt > 30 microbubbles, at rest or during provocative manoeuvres, by TTE ou TOE associated ASA (base ≥ à 15 mm, total excursion > à 10 mm) by TOE Informed consent. Exclusion Criteria: Any identifiable cause of ischemic stroke other than PFO. Isolated atrial septal defect or atrial septal defect associated with PFO with significant left-to-right shunt requiring closure. Previous surgical or endovascular treatments of PFO or ASA. Known or suspected pregnancy (beta hCG test must be performed before inclusion). Women who are breast-feeding. Inability to comply with the treatments or follow-up requirements of the study. No affiliation to the national health service. Presence of other medical problems that would either lead to inability to complete the trial or interfere with the assessment of outcomes. Participation in another study. Unable to understand the full meaning of the informed consent. Related medical treatments of the trial: Long-term oral anticoagulation or antiplatelet therapy is indicated for another disease. Contra-indication to antiplatelet therapy or oral anticoagulants : 3-arm trial : contra-indication to aspirin or clopidogrel or antivitamins K 2-arm trial (closure vs antiplatelet therapy) : contra-indication to aspirin or clopidogrel 2-arm trial (antivitamins K vs antiplatelet therapy : contra-indication to antivitamins K or to any antiplatelet drug Increased risk of bleeding, such as severe hepatic insufficiency, current peptic ulceration, proliferative diabetic retinopathy, history of severe systemic bleeding (e.g. gastrointestinal bleeding, gross hematuria, intraocular bleeding, hemorrhagic stroke, or intracranial hemorrhage), or other history of bleeding diathesis or coagulopathy. Related to endovascular treatments : Infection requiring antibiotics (inclusion is possible after healing, 4 weeks after withdrawal of antibiotics). Very large or multi-perforated ASA for which endovascular treatments is deemed too risky. Presence of thrombus or occlusion between the venous access and the right atrium. Presence of an inferior vena cava filter. Severe pulmonary hypertension.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
MAS Jean-Louis, MD, PhD
Organizational Affiliation
Centre hospitalier sainte Anne
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hôpital Saint-Anne
City
Paris
Country
France

12. IPD Sharing Statement

Citations:
PubMed Identifier
28902593
Citation
Mas JL, Derumeaux G, Guillon B, Massardier E, Hosseini H, Mechtouff L, Arquizan C, Bejot Y, Vuillier F, Detante O, Guidoux C, Canaple S, Vaduva C, Dequatre-Ponchelle N, Sibon I, Garnier P, Ferrier A, Timsit S, Robinet-Borgomano E, Sablot D, Lacour JC, Zuber M, Favrole P, Pinel JF, Apoil M, Reiner P, Lefebvre C, Guerin P, Piot C, Rossi R, Dubois-Rande JL, Eicher JC, Meneveau N, Lusson JR, Bertrand B, Schleich JM, Godart F, Thambo JB, Leborgne L, Michel P, Pierard L, Turc G, Barthelet M, Charles-Nelson A, Weimar C, Moulin T, Juliard JM, Chatellier G; CLOSE Investigators. Patent Foramen Ovale Closure or Anticoagulation vs. Antiplatelets after Stroke. N Engl J Med. 2017 Sep 14;377(11):1011-1021. doi: 10.1056/NEJMoa1705915.
Results Reference
result
PubMed Identifier
32381162
Citation
Turc G, Lee JY, Brochet E, Kim JS, Song JK, Mas JL; CLOSE and DEFENSE-PFO Trial Investigators. Atrial Septal Aneurysm, Shunt Size, and Recurrent Stroke Risk in Patients With Patent Foramen Ovale. J Am Coll Cardiol. 2020 May 12;75(18):2312-2320. doi: 10.1016/j.jacc.2020.02.068.
Results Reference
derived
PubMed Identifier
29910193
Citation
Turc G, Calvet D, Guerin P, Sroussi M, Chatellier G, Mas JL; CLOSE Investigators. Closure, Anticoagulation, or Antiplatelet Therapy for Cryptogenic Stroke With Patent Foramen Ovale: Systematic Review of Randomized Trials, Sequential Meta-Analysis, and New Insights From the CLOSE Study. J Am Heart Assoc. 2018 Jun 17;7(12):e008356. doi: 10.1161/JAHA.117.008356.
Results Reference
derived
PubMed Identifier
27056964
Citation
Mas JL, Derumeaux G, Amarenco P, Arquizan C, Aubry P, Barthelet M, Bertrand B, Brochet E, Cabanes L, Donal E, Dubois-Rande JL, Durand-Zaleski I, Ernande L, Finet G, Fraisse A, Giroud M, Guerin P, Habib G, Juliard JM, Leys D, Lievre M, Lusson JR, Marcon F, Michel P, Moulin T, Mounier-Vehier F, Pierard L, Piot C, Rey C, Rodier G, Roudaut R, Schleich JM, Teiger E, Turc G, Vuillier F, Weimar C, Woimant F, Chatellier G; CLOSE investigators. close: Closure of patent foramen ovale, oral anticoagulants or antiplatelet therapy to prevent stroke recurrence: Study design. Int J Stroke. 2016 Aug;11(6):724-32. doi: 10.1177/1747493016643551. Epub 2016 Apr 7.
Results Reference
derived

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Patent Foramen Ovale Closure or Anticoagulants Versus Antiplatelet Therapy to Prevent Stroke Recurrence

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