CLOSE Trial: PFO Closure or Anticoagulation vs Antiplatelets for Cryptogenic Stroke (Mas et al., 2017)
In patients 16–60 with cryptogenic ischemic stroke and a PFO carrying high-risk morphology (atrial septal aneurysm or large interatrial shunt), does transcatheter PFO closure plus long-term antiplatelet therapy reduce recurrent stroke compared with antiplatelet therapy alone?
Mas JL et al. (NEJM 2017;377:1011-1021) · doi:10.1056/NEJMoa1705915 · 663 patients
Population
Included
- Age 16–60 years
- Recent ischemic stroke within 6 months with no identifiable cause other than PFO
- PFO with atrial septal aneurysm (septum primum excursion >10 mm on TEE) OR large interatrial shunt (>30 microbubbles within 3 cardiac cycles on TEE with agitated saline)
- Workup excluded large-artery atherosclerosis, established cardioembolic source, small-vessel/lacunar disease, hypercoagulable state, and arterial dissection
Core inclusion
- Age 16 to 60 years
- Ischaemic stroke within the previous 6 months with no identifiable cause other than a PFO
- Ischaemic stroke defined as acute focal neurologic symptoms with a recent cerebral infarct on brain imaging, regardless of symptom duration
Required PFO morphology (one of)
- PFO with an associated atrial septal aneurysm, defined by a septum primum excursion greater than 10 mm on transoesophageal echocardiography
- PFO with a large interatrial shunt, defined by more than 30 microbubbles in the left atrium within 3 cardiac cycles after opacification of the right atrium on transoesophageal echocardiography with agitated saline
Required exclusion of competing causes
- Investigations used to rule out alternative causes of stroke (large-artery atherosclerosis, established cardioembolic source, small-vessel or lacunar disease, hypercoagulable state, and arterial dissection)
Excluded
- Other identifiable cause of stroke
- Indication mandating anticoagulation (or, alternatively, contraindication to either anticoagulation or PFO closure. Assigned to one of two restricted randomization groups)
- Age outside 16–60
Exclusions
- Any other identifiable cause of stroke
- Age outside 16 to 60 years
- Contraindication to oral anticoagulation (randomly assigned to PFO closure or to antiplatelet therapy only, randomization group 2)
- Contraindication to PFO closure (randomly assigned to anticoagulation or to antiplatelet therapy only, randomization group 3)
Source: Mas et al., N Engl J Med 2017;377:1011-1021· Retrieved 2026-06-09
Primary Outcome
Fatal or nonfatal recurrent stroke at mean 5.3-year follow-up
Negligible absolute difference
Recurrent stroke at 5 years
Study Arms
- Agent
- Transcatheter PFO closure device plus antiplatelet therapy
- Dose
- Dual antiplatelet aspirin 75 mg plus clopidogrel 75 mg daily for the first 3 months, then single antiplatelet thereafter
- Route
- Percutaneous transcatheter device implantation; oral antiplatelet therapy
- Frequency
- Single closure procedure; daily antiplatelet therapy
- Duration
- Long-term antiplatelet therapy throughout the trial after closure
- Co-interventions
- 11 different implantable closure devices were used, selected by experienced interventional cardiologists per the Interventional Cardiology Committee; single antiplatelet options after month 3 were aspirin, clopidogrel, or aspirin plus extended-release dipyridamole
Intervention arm of the PFO closure versus antiplatelet comparison (randomization groups 1 and 2 combined).
- Agent
- Antiplatelet therapy
- Dose
- Site-chosen single antiplatelet regimen
- Route
- Oral
- Frequency
- Daily
- Duration
- Throughout the trial
- Co-interventions
- Options were aspirin, clopidogrel, or aspirin plus extended-release dipyridamole
Control arm for the primary PFO closure comparison.
- Agent
- Oral anticoagulant
- Dose
- Vitamin K antagonist titrated to target INR 2 to 3, or a direct oral anticoagulant at standard dose
- Route
- Oral
- Frequency
- Daily
- Duration
- Throughout the trial
- Co-interventions
- Compared with antiplatelet therapy alone using combined data from randomization groups 1 and 3; this comparison was underpowered
Parallel anticoagulation question, not the primary comparison. 3 of 187 strokes on anticoagulation versus 7 of 174 on antiplatelet alone; HR 0.44 (95% CI 0.11 to 1.85); statistical significance was not analysed.
Safety
Atrial fibrillation or flutter
4.6%
0.9%
AF/flutter: 11/238 (4.6%) PFO closure vs 2/235 (0.9%) antiplatelet, P=0.02. 10 of 11 closure-arm AF cases occurred within 30 days of procedure; AF did not recur during median 4.4-year follow-up. Predominantly transient periprocedural AF, not a durable arrhythmic substrate. Source: Mas et al., NEJM 2017, Table 3.
Trial Design
Type
- Investigator-initiated, multicenter, open-label, three-randomization-group superiority trial
- Blinded outcome adjudication by clinical events committee
- 1:1:1 randomization (PFO closure + antiplatelet | antiplatelet | oral anticoagulation), with restricted 1:1 randomization for patients with contraindication to one arm
- 32 sites in France and 2 sites in Germany
- Stratified by participating center, randomization group, and septal anomaly type (ASA vs large shunt)
- Two one-sided superiority hypotheses with Bonferroni adjustment (alpha 0.035 per hypothesis)
- Enrollment stopped early administratively (December 2014) due to sponsor budget; follow-up continued
Timeline
Enrolled December 2007 to December 2016; mean follow-up 5.3 years
N
663
Enrollment
663 patients (groups 1+2: N=473 for the PFO closure vs antiplatelet comparison) at 32 French + 2 German sites. Enrolled December 2007 to December 2016. Mean follow-up 5.3 years. Published NEJM 2017.
ClinicalTrials.gov
NCT00562289Bedside Pearl
CLOSE: in patients 16–60 with cryptogenic stroke and a PFO carrying high-risk features (atrial septal aneurysm OR large shunt), PFO closure + antiplatelet abolished recurrent stroke vs antiplatelet alone (0 vs 14 events over 5y, HR 0.03, NNT 20). Atrial fibrillation rose to 4.6% but was largely transient periprocedural. Read with RESPECT long-term and REDUCE (same NEJM 2017 issue).