DEFENSE-PFO
Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients With High-Risk Patent Foramen Ovale
Year of Publication: 2018
Authors: Pil Hyung Lee, Jae-Kwan Song, Jong S. Kim, ..., Seung-Jung Park
Journal: Journal of the American College of Cardiology
Citation: J Am Coll Cardiol 2018;71(20):2335-42
Link: https://doi.org/10.1016/j.jacc.2018.02.046
PDF: https://www.jacc.org/doi/epdf/10.1016/j.jacc.2018.02.046
PDF: Clinical Question
In patients with cryptogenic stroke and high-risk PFO (defined by specific morphologic characteristics on TEE), does transcatheter PFO closure combined with medical therapy result in lower rates of recurrent stroke compared to medical therapy alone?
Bottom Line
In patients with cryptogenic stroke and high-risk PFO characteristics (large size ≥2mm, atrial septal aneurysm, or hypermobility ≥10mm), PFO closure resulted in significantly lower rates of stroke recurrence (0% vs 10.5%, p=0.023) and the composite primary endpoint (0% vs 12.9%, p=0.013) compared to medical therapy alone over 2 years of follow-up.
Major Points
- Multicenter, randomized, open-label trial comparing PFO closure + medical therapy vs medical therapy alone
- Enrolled 120 patients with cryptogenic stroke and high-risk PFO features defined by TEE
- High-risk features: PFO size ≥2mm, atrial septal aneurysm (≥15mm protrusion), or hypermobility (≥10mm septal excursion)
- All 53 PFO closures were successful using Amplatzer PFO Occluder
- Primary endpoint (stroke, vascular death, or major bleeding) occurred in 0% of PFO closure group vs 12.9% of medication-only group (p=0.013)
- Ischemic stroke recurrence: 0% vs 10.5% (p=0.023)
- Number needed to treat: 10 patients to prevent 1 stroke at 2 years
- Trial terminated early due to safety concerns after publication of CLOSE trial with similar design
- Procedural complications included atrial fibrillation (n=2), pericardial effusion (n=1), and pseudoaneurysm (n=1)
- Results support morphologic risk stratification to select optimal candidates for PFO closure
Design
Study Type: Multicenter, randomized, open-label, superiority trial
Randomization: 1
Blinding: Open-label with masked outcome assessment
Enrollment Period: September 2011 to October 2017
Follow-up Duration: Median 2.8 years (IQR: 0.9-4.1 years)
Centers: 2
Countries: South Korea
Sample Size: 120
Analysis: Intention-to-treat analysis using Kaplan-Meier survival curves compared with log-rank test; Per-protocol analysis also performed (109 patients)
Inclusion Criteria
- Ischemic stroke within previous 6 months with no identifiable cause other than high-risk PFO
- Acute focal neurologic deficit lasting ≥24 hours OR evidence of relevant infarction on brain MRI
- High-risk PFO defined by TEE: PFO with atrial septal aneurysm (protrusion ≥15mm beyond level surface of atrial septum) OR hypermobility (phasic septal excursion ≥10mm into either atrium) OR PFO size ≥2mm (maximum separation of septum primum from secundum during Valsalva)
- Right-to-left shunting demonstrated with agitated saline at rest or during Valsalva maneuver
Exclusion Criteria
- Large-artery atherosclerotic disease (≥50% stenosis or occlusion of major vessel)
- Small-vessel occlusive disease (infarction <1.5cm diameter or typical lacunar syndrome)
- Established cardioembolic source
- Paroxysmal atrial fibrillation on Holter or prolonged cardiac rhythm monitoring
- Hypercoagulable disorder requiring anticoagulation
- Arterial dissection
- History of myocardial infarction or unstable angina
- History of intracranial bleeding
- Pre-existing neurological disorders
- Left ventricular systolic dysfunction with aneurysm or akinesia
- Contraindications to antiplatelet therapy
- Underlying malignant disease
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| N | 60 | 60 |
| Age (years) | 54 ± 12 | 49 ± 15 |
| Male | 56.7% | 55.0% |
| Hypertension | 28.3% | 20.0% |
| Diabetes | 13.3% | 10.0% |
| Current smoker | 26.7% | 16.7% |
| Hypercholesterolemia | 41.7% | 30.0% |
| Anterior circulatory territory | 56.7% | 46.7% |
| Multiple territories | 3.3% | 0% |
| Modified Rankin scale 0-1 | 75.0% | 78.3% |
| Modified Rankin scale 2-3 | 25.0% | 21.7% |
| PFO size (mm) | 3.2 ± 1.1 | 3.2 ± 1.5 |
| Atrial septal aneurysm | 13.3% | 8.3% |
| Atrial septal hypermobility | 45.0% | 46.7% |
Arms
| Field | Control | PFO Closure Group |
|---|---|---|
| Intervention | Medical therapy alone with antiplatelet therapy (aspirin 100mg daily alone, or combined with clopidogrel 75mg daily or cilostazol 200mg daily) or warfarin (target INR 2.0-3.0) at investigator discretion | Transcatheter PFO closure using Amplatzer PFO Occluder plus medical therapy. Generally dual antiplatelet therapy (aspirin 100mg + clopidogrel 75mg daily) for at least 6 months post-procedure, though investigators could choose anticoagulation based on individual risk-benefit assessment |
| Duration | 2 years follow-up | 2 years follow-up |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Composite of stroke, vascular death, or TIMI-defined major bleeding during 2 years of follow-up | Primary | 6 events; 2-year Kaplan-Meier rate 12.9% (95% CI: 3.2-22.6%) | 0 events; 2-year Kaplan-Meier rate 0% | 12.90% | 0.013 |
| Ischemic stroke | Secondary | 5 events; 2-year Kaplan-Meier rate 10.5% (95% CI: 1.68-19.32%) | 0 events; 2-year rate 0% | 0.023 | |
| Vascular death | Secondary | 0 events | 0 events | NA | |
| TIMI-defined major bleeding | Secondary | 2 events; 2-year Kaplan-Meier rate 4.9% | 0 events; 2-year rate 0% | 0.15 | |
| Hemorrhagic stroke | Secondary | 1 event; 2-year Kaplan-Meier rate 2.5% | 0 events; 2-year rate 0% | 0.30 | |
| Transient ischemic attack | Secondary | 1 event; 2-year Kaplan-Meier rate 2.0% | 0 events; 2-year rate 0% | 0.32 | |
| Systemic embolism | Secondary | 0 events | 0 events | NA | |
| New ischemic lesion on follow-up MRI | Secondary | 7/38 patients (18.4%) | 3/34 patients (8.8%) | 0.24 | |
| Atrial fibrillation | Adverse | 0 | 2 | ||
| Pericardial effusion | Adverse | 0 | 1 | ||
| Pseudoaneurysm at puncture site | Adverse | 0 | 1 |
Subgroup Analysis
In the medication-only group, recurrent strokes occurred during dual antiplatelet therapy (n=2), single antiplatelet therapy (n=1), and warfarin (n=1). Atrial septal aneurysm or hypermobility was present in 4 of 5 patients with recurrent stroke. Three patients showed new lesions in different vascular territories from the initial lesion.
Criticisms
- Early termination due to safety concerns after publication of CLOSE trial, resulting in underpowered study (120 enrolled vs 210 planned)
- Open-label design, though outcome assessment was masked
- Only 2 centers in South Korea, limiting generalizability
- Seven patients randomized to PFO closure declined the intervention
- Four patients in medication-only group crossed over to receive PFO closure during follow-up
- Follow-up MRI was performed in only 60% of patients (72/120)
- Potential selection bias due to single-country enrollment
- Medication choice was at investigator discretion, introducing treatment heterogeneity
- Unable to calculate hazard ratio due to zero events in intervention arm
- Relatively short median follow-up (2.8 years) compared to some other PFO trials
Funding
Cardiovascular Research Foundation, Seoul, South Korea
Based on: DEFENSE-PFO (Journal of the American College of Cardiology, 2018)
Authors: Pil Hyung Lee, Jae-Kwan Song, Jong S. Kim, ..., Seung-Jung Park
Citation: J Am Coll Cardiol 2018;71(20):2335-42
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