Patent Foramen Ovale Closure or Anticoagulants vs. Antiplatelet Therapy to Prevent Stroke Recurrence - CLOSE

Contribution To Literature:

The CLOSE trial showed that PFO closure was superior to antiplatelet therapy at preventing recurrent strokes.

Description:

The goal of the trial was to evaluate patent foramen ovale (PFO) closure versus anticoagulation versus antiplatelet therapy among patients with cryptogenic stroke attributable to PFO and high-risk characteristics for recurrent stroke.

Study Design

  • Randomized
  • Parallel
  • Stratified

Patients with cryptogenic stroke attributable to PFO were randomized within three groups:

  • Group 1 patients had no contraindications to closure or anticoagulation and were randomized to PFO closure versus anticoagulation versus antiplatelet therapy.
  • Group 2 patients had contraindications to anticoagulation and were randomized to PFO closure versus antiplatelet therapy.
  • Group 3 patients had contraindications to closure and were randomized to anticoagulation versus antiplatelet therapy.

Patients were combined so that PFO closure was compared to antiplatelet therapy, and anticoagulation therapy was compared to antiplatelet therapy. All patients received aspirin plus clopidogrel for 3 months, then long-term aspirin therapy.

  • Total number of enrollees: 663
  • Duration of follow-up: mean 5.3 years
  • Mean patient age: 43 years
  • Percentage female: 42%
  • Percentage with diabetes: 1.3%

Inclusion criteria:

  • Patients with cryptogenic stroke between 16 and 60 years of age
  • Associated atrial septal aneurysm (>10 mm excursion) or large interatrial shunt (>30 microbubbles in the left atrium within three cardiac cycles)

Exclusion criteria:

  • Another cause for stroke associated with PFO
  • Isolated atrial septal defect (ASD) or ASD associated with PFO but with a hemodynamically significant left-to-right shunt requiring closure
  • Previous surgical or endovascular treatments of PFO or atrial septal aneurysm

Principal Findings:

The primary outcome (intention-to-treat analysis), number of fatal or nonfatal ischemic strokes, occurred in 0 of the PFO closure group versus 14 of the antiplatelet-only group (p < 0.001).

The primary outcome (intention-to-treat analysis), number of fatal or nonfatal ischemic strokes, occurred in three of the anticoagulation group versus seven of the antiplatelet-only group (p = not significant [NS]).

Secondary outcomes:

  • The number of fatal or nonfatal ischemic strokes (per-protocol analysis): 0 of the PFO closure group versus 14 of the antiplatelet-only group (p < 0.001)
  • The number of fatal or nonfatal ischemic strokes (per-protocol analysis): two of the anticoagulation group versus seven of the antiplatelet only group (p = NS)
  • Incidence of atrial fibrillation: 4.6% of the PFO closure group versus 0.9% of the antiplatelet-only group (p = 0.02); 10 of the 11 patients with new-onset atrial fibrillation were treated with anticoagulation
  • Incidence of atrial fibrillation: 0% of the anticoagulation group versus 1.1% of the antiplatelet-only group (p = 0.23)

Interpretation:

Among patients with cryptogenic stroke and high-risk characteristics (atrial septal aneurysm or large right-to-left shunt), PFO closure was superior to antiplatelet therapy at preventing recurrent stroke. Anticoagulation versus antiplatelet therapy was inconclusive. PFO closure was associated with a higher incidence of atrial fibrillation compared with antiplatelet therapy. The occurrence of atrial fibrillation and subsequent use of anticoagulation confounds the association between PFO closure and stroke recurrence.

Previous trials on the topic have been inconclusive regarding the efficacy of PFO closure at preventing recurrent stroke. A strength of this trial is the selection of high-risk cryptogenic stroke patients and exclusion of patients with potential alternative explanations for stroke. Among these young patients, the long-term risk from the higher incidence of atrial fibrillation with PFO closure needs to be considered.

References:

Mas JL, Derumeaux G, Guillon B, et al., on behalf of the CLOSE Investigators. Patent Foramen Ovale Closure or Anticoagulation vs. Antiplatelets After Stroke. N Engl J Med 2017;377:1011-21

Editorial: Ropper AH. Tipping Point for Patent Foramen Ovale Closure. N Engl J Med 2017;377:1093-5.


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