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

Assistance Publique - Hôpitaux de Paris

Status and phase: Not yet enrolling; Phase 3

Conditions: Cryptogenic Ischemic Stroke; Patent Foramen Ovale

Treatments: Procedure: Transcatheter PFO closure; Drug: Oral Anticoagulant, Direct-Acting; Drug: Antiplatelet therapy

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT05387954

PHRC-20-0680 (Other Identifier)

2021-A03197-34 (Other Identifier)

APHP211041

Details and patient eligibility

About

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.

Full 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.

Enrollment: 792 estimated patients

Sex: All

Ages: 60 to 80 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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792 participants in 3 patient groups

Antiplatelet therapy

Active Comparator group

Description:

Aspirin OR clopidogrel

Treatment:

Drug: Antiplatelet therapy

Oral anticoagulants, Direct-Acting

Experimental group

Description:

Apixaban (5mg twice a day) OR Dabigatran (150 mg twice a day) OR Rivaroxaban (20 mg once a day)

Treatment:

Drug: Oral Anticoagulant, Direct-Acting

PFO closure

Experimental group

Description:

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

Treatment:

Drug: Antiplatelet therapy

Procedure: Transcatheter PFO closure