CLOSE
Patent Foramen Ovale Closure or Anticoagulation vs Antiplatelets after Stroke
Year of Publication: 2017
Authors: Mas, Jean-Luc et al.
Journal: New England Journal of Medicine
Citation: N Engl J Med 2017;377:1011–1021
PDF: Clinical Question
In patients with recent cryptogenic stroke and PFO, is PFO closure superior to antiplatelet therapy in preventing recurrent stroke?
Study Overview
Objective
Compare PFO closure or anticoagulation versus antiplatelet therapy in patients with cryptogenic stroke and high-risk PFO features.
Study Summary
PFO closure significantly reduced stroke recurrence compared to antiplatelets alone in patients aged 16–60 with cryptogenic stroke and either atrial septal aneurysm or large interatrial shunt.
Intervention
- Three-arm randomized trial comparing:
- PFO closure + antiplatelet therapy
- Oral anticoagulation (VKA or DOAC)
- Antiplatelet therapy alone. Mean follow-up: 5.3 years.
Bottom Line
PFO closure significantly reduced recurrent stroke compared with antiplatelet therapy in select patients with cryptogenic stroke.
Major Points
- One of three landmark 2017 PFO closure RCTs (with RESPECT and REDUCE). Unique design: three-arm trial comparing PFO closure vs antiplatelet therapy vs oral anticoagulation — the only PFO trial to include an anticoagulation arm.
- Strictest patient selection among PFO trials: required PFO with either atrial septal aneurysm (ASA, septum primum excursion >10 mm) OR large interatrial shunt (>30 microbubbles) — enriching for 'high-risk' PFO anatomy.
- Zero recurrent strokes in the PFO closure group (0/238) vs 14 in the antiplatelet group (14/235) over mean 5.3 years follow-up (HR 0.03; 95% CI 0-0.26; P<0.001). This 0-event result was the most dramatic outcome of any PFO trial.
- New-onset atrial fibrillation or flutter occurred in 4.6% of closure patients vs 0.9% antiplatelet (P=0.02) — most cases within 1 month of the procedure and generally transient.
- Anticoagulation vs antiplatelet analysis (ITT): 3 strokes in anticoagulation group (3/187) vs 7 in antiplatelet group (7/174), HR 0.44 (95% CI 0.11–1.48); statistical significance was not analyzed because the study was not adequately powered to compare these groups.
- Devices used: 11 different PFO closure devices permitted (not limited to one manufacturer).
- Conducted in France and Germany (34 sites total: 32 in France, 2 in Germany). Enrollment ran December 2007–December 2014 (~7 years) and was stopped early below the 900-patient target due to slow accrual and budget constraints; follow-up continued to December 2016.
- Youngest PFO trial population (mean age ~43) with very low vascular risk factor prevalence (hypertension ~10–11%, diabetes ~1–4%) — ideal cryptogenic stroke population.
Design
Study Type: Open-label randomized controlled trial
Randomization: 1
Blinding: Open-label
Enrollment Period: December 2007 – December 2014
Follow-up Duration: Mean 5.3 years
Centers: 34
Countries: France, Germany
Sample Size: 663
Analysis: Intention-to-treat
Inclusion Criteria
- Age 16–60 years.
- Recent cryptogenic ischemic stroke (within 6 months of randomization).
- PFO with associated atrial septal aneurysm (ASA, septum primum excursion >10 mm) OR large interatrial shunt (>30 microbubbles on contrast transesophageal echocardiography).
- TEE confirmation of PFO anatomy (reviewed centrally by two echocardiographers).
- Complete etiological workup excluding other stroke causes: brain MRI, cervical/intracranial vascular imaging, ECG + ≥24h cardiac monitoring, standard blood tests.
Exclusion Criteria
- Identifiable cause of stroke (large-vessel atherosclerosis, cardioembolic source, lacunar mechanism, vasculitis, dissection).
- Small PFO without ASA and without large shunt.
- Chronic atrial fibrillation or flutter.
- Indication for long-term anticoagulation.
- Contraindication to antiplatelet therapy.
- Prior PFO closure attempt.
- Severe disability from index stroke.
- Pregnancy or planned pregnancy.
- Note: patients with contraindications to oral anticoagulation (n=129) or to PFO closure (n=10) were not excluded — they were assigned to two-arm sub-randomizations (groups 2 and 3, respectively).
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| Mean age ± SD - yr | 43.8 ± 10.5 | 42.9 ± 10.1 |
| Male sex - % | 60.4 | 57.6 |
| Hypertension - % | 10.2 | 11.3 |
| Diabetes mellitus - % | 3.8 | 1.3 |
| Hypercholesterolemia - % | 15.3 | 12.6 |
| Current smoker - % | 29.4 | 28.6 |
| Prior stroke - % | 3.0 | 4.2 |
| Migraine - % | 33.2 | 28.2 |
| Atrial septal aneurysm - % | 31.5 | 34.0 |
| Large shunt (>30 microbubbles) - % | 94.9 | 90.8 |
| Both ASA and large shunt - % | 26.4 | 24.8 |
Arms
| Field | PFO Closure + Antiplatelet | Control | Oral Anticoagulation |
|---|---|---|---|
| Intervention | Percutaneous PFO closure using any CE-marked device (11 different devices used across the trial). Post-procedure: dual antiplatelet therapy (aspirin 75 mg + clopidogrel 75 mg per day) for 3 months, followed by long-term single antiplatelet therapy. Contrast echocardiography at 6–12 months to confirm closure. | Antiplatelet therapy at investigator discretion: aspirin, clopidogrel, or aspirin combined with extended-release dipyridamole (not strictly monotherapy, since aspirin + dipyridamole is a permitted regimen). Therapy continued for the entire follow-up period. | Oral anticoagulation with either a vitamin K antagonist (target INR 2.0–3.0; used in 93% of patients) or a direct oral anticoagulant (dabigatran, rivaroxaban, or apixaban; used in 7%). Patients with a contraindication to PFO closure (randomization group 3) were assigned between anticoagulation and antiplatelet-only. |
| Duration | Mean 5.3 years; device is permanent | Mean 5.3 years | Mean 5.4 years |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Occurrence of fatal or nonfatal stroke | Primary | 14/235 (4.9% KM at 5yr) | 0/238 (0% at 5yr) | 0.03 | <0.001 |
| Composite: ischemic stroke, TIA, or systemic embolism | Secondary | 8.9% (21/235) | 3.4% (8/238) | HR 0.39 (95% CI 0.16–0.82) | 0.01 |
| Major or fatal device-related or procedure-related complications | Adverse | 5.9% (14/238) | |||
| Atrial fibrillation or flutter | Adverse | 0.9% (2/235) | 4.6% (11/238) | 0.02 | |
| Serious adverse events (≥1) | Adverse | 33.2% (78/235) | 35.7% (85/238) | 0.56 | |
| Major or fatal bleeding | Adverse | 2.1% (5/235) | 0.8% (2/238) | 0.28 |
Subgroup Analysis
No evidence of heterogeneity of treatment effect across pre-specified subgroups (age, sex, ASA vs. large shunt, prior cerebrovascular event, RoPE score). Among the 14 recurrent strokes in the antiplatelet-only group, 9 occurred among the 74 patients (12.2%) with both PFO and ASA, and 5 occurred among the 161 patients (3.1%) with a large PFO without ASA — suggesting ASA is a stronger risk marker. The 0-event closure arm precluded formal HR calculation within subgroups. Anticoagulation arm (ITT): 3 strokes in 187 patients (3/187) vs 7/174 in antiplatelet arm, HR 0.44 (95% CI 0.11–1.48); statistical significance was not analyzed because the study was not adequately powered to compare these groups. New-onset AF or flutter in 4.6% post-closure, mostly within 1 month, suggesting device-related atrial irritation.
Criticisms
- Open-label design — patients and physicians knew treatment assignment, potentially influencing care decisions and outcome reporting.
- Extremely selective enrollment: required ASA or large shunt, limiting generalizability to broader PFO populations.
- Enrollment stopped early below the 900-patient target due to slow accrual and budget constraints — trial ultimately underpowered relative to its original design.
- 7-year enrollment period (2007–2014) — prolonged accrual raises concerns about evolving diagnostic standards, cardiac monitoring technology, and background medical therapy.
- Zero events in closure group create wide confidence intervals (upper bound of HR CI = 0.26) and prevent precise effect-size quantification, particularly within subgroups.
- Complex three-group randomization scheme (based on contraindications) — patients with contraindications to closure or anticoagulation were assigned to different two-arm randomizations, complicating interpretation.
- No mandatory prolonged cardiac monitoring (only ≥24 h required) — modern practice uses 30-day or implantable loop monitors, potentially missing occult AF as an alternative stroke etiology.
- Age cap of 60 years — excludes older cryptogenic stroke patients where age-related AF prevalence is higher.
- New-onset AF rate of 4.6% post-closure is concerning — while mostly transient, long-term AF risk after device implantation remains unclear.
- Anticoagulation vs antiplatelet comparison was underpowered (HR 0.44, wide 95% CI 0.11–1.48); the authors did not analyze statistical significance for this comparison, so no formal conclusion can be drawn.
Funding
French Ministry of Health (grant P060406)
Based on: CLOSE (New England Journal of Medicine, 2017)
Authors: Mas, Jean-Luc et al.
Citation: N Engl J Med 2017;377:1011–1021
Content summarized and formatted by NeuroTrials.ai.