REDUCE Trial: PFO Closure with Gore HELEX/Cardioform vs Antiplatelet Therapy for Cryptogenic Stroke (Søndergaard et al., 2017)
In patients 18–59 with cryptogenic ischemic stroke and a PFO, does transcatheter closure with Gore HELEX or Cardioform plus antiplatelet therapy reduce recurrent clinical stroke compared with antiplatelet therapy alone? Anticoagulation was not permitted in the comparator, giving the cleanest antiplatelet head-to-head of the 2017 PFO trio.
Søndergaard L et al. (NEJM 2017;377:1033-1042) · doi:10.1056/NEJMoa1707404 · 664 patients
Population
Included
- Age 18–59 years
- Cryptogenic ischemic stroke within 180 days (acute focal neurologic deficit ≥24 hours OR imaging-confirmed infarct)
- TEE-confirmed PFO with right-to-left shunt
- Workup excluded large-artery atherosclerosis (≥50% major-vessel stenosis or occlusion), established cardioembolic source, small-vessel/lacunar disease (<1.5 cm deep infarct or typical lacunar syndrome), hypercoagulable disorder requiring anticoagulation, arterial dissection
Core inclusion
- Age 18 to 59 years
- Cryptogenic ischaemic stroke within 180 days before randomisation
- Ischaemic stroke defined as an acute focal neurologic deficit, presumably due to ischaemia, that either resulted in clinical symptoms lasting 24 hours or more or was associated with evidence of relevant infarction on MRI (or CT if MRI could not be performed)
- A PFO with a right-to-left shunt assessed by transoesophageal echocardiography with agitated saline at rest or during a Valsalva manoeuvre
Required exclusion of competing causes
- Index stroke defined as cryptogenic after ruling out other identifiable mechanisms (large-artery atherosclerotic disease, established cardioembolic source, small-vessel occlusive [lacunar] disease, hypercoagulable disorder requiring anticoagulation, or arterial dissection)
- Vessel imaging of the intracranial arteries, cervical arteries, and aortic arch performed to assess for large-artery atherosclerotic disease
Excluded
- Identified competing stroke mechanism (per inclusion criteria workup)
- Specific indication for anticoagulation
- Uncontrolled diabetes mellitus or hypertension
- Autoimmune disease
- Recent alcohol or drug abuse
- Age outside 18–59
Exclusions
- Stenosis of 50% or more of the diameter of a major vessel, or occlusion of a major vessel
- Stroke as a result of small-vessel occlusive disease (a small deep infarct under 1.5 cm in diameter, or a typical clinical lacunar syndrome)
- A specific indication for anticoagulation
- Uncontrolled diabetes mellitus
- Uncontrolled hypertension
- Autoimmune disease
- A recent history of alcohol or drug abuse
- Age outside 18 to 59 years
Source: Sondergaard et al., N Engl J Med 2017;377:1033-1042· Retrieved 2026-06-09
Primary Outcome
Clinical ischemic stroke at median 3.2-year follow-up
Negligible absolute difference
Clinical stroke at 3.2y
Study Arms
- Agent
- Gore HELEX Septal Occluder (through late 2012) or Gore Cardioform Septal Occluder (from late 2012 onward), plus antiplatelet therapy
- Dose
- Single device implantation; clopidogrel 300 mg loading dose then 75 mg daily for 3 days post-procedure, followed by the site-chosen antiplatelet regimen
- Route
- Percutaneous transcatheter device implantation; oral antiplatelet therapy
- Frequency
- Single closure procedure (attempted within 90 days of randomisation); daily antiplatelet therapy
- Duration
- Antiplatelet therapy continued for the duration of follow-up
- Co-interventions
- Antiplatelet regimen was the same as the antiplatelet-only group at each site: aspirin 75 to 325 mg daily, aspirin 50 to 100 mg plus dipyridamole 225 to 400 mg daily, or clopidogrel 75 mg daily
Randomised 2:1 to PFO closure versus antiplatelet therapy alone.
- Agent
- Antiplatelet therapy
- Dose
- Site-chosen single regimen
- Route
- Oral
- Frequency
- Daily
- Duration
- For the duration of follow-up
- Co-interventions
- Options were aspirin 75 to 325 mg daily, aspirin 50 to 100 mg plus dipyridamole 225 to 400 mg daily, or clopidogrel 75 mg daily; other combinations of antiplatelet drugs and anticoagulants were not permitted
Clean antiplatelet comparator. Anticoagulation was not permitted in either group.
Safety
Atrial fibrillation or flutter
6.6%
0.4%
Atrial fibrillation/flutter: 29/441 (6.6%) PFO closure vs 1/223 (0.4%) antiplatelet alone, P<0.001. Largest absolute AF signal of the three 2017 PFO trials. 83% of closure-arm AF detected within 45 days of procedure; 59% resolved within 2 weeks of onset. Predominantly transient periprocedural AF. 1 of 29 patients with post-closure AF had a recurrent stroke. Source: Søndergaard et al., NEJM 2017, Table 3.
Trial Design
Type
- Multinational, prospective, randomized, controlled, open-label superiority trial with blinded outcome adjudication
- 2:1 randomization (PFO closure + antiplatelet : antiplatelet alone)
- 63 sites in Canada, Denmark, Finland, Norway, Sweden, UK, US
- Two coprimary endpoints: (1) freedom from clinical ischemic stroke through ≥24 months; (2) 24-month incidence of new brain infarction (clinical OR silent on T2 MRI)
- Multiplicity adjustment: Dubey and Armitage–Parmar procedure
- Statistical analysis plan revised mid-trial (without unblinding) to add the new-brain-infarction coprimary and rescind the planned interim analysis after CLOSURE-I/PC/RESPECT reported lower-than-expected event rates
- Clean antiplatelet comparator. Anticoagulation not permitted
Timeline
Enrolled December 2008 to February 2015; median follow-up 3.2 years (IQR 2.2–4.8); primary analysis April 24, 2017
N
664
Enrollment
664 patients (441 PFO closure : 223 antiplatelet, 2:1 ratio) at 63 sites in Canada, Denmark, Finland, Norway, Sweden, UK, US. Coprimary endpoints: clinical ischemic stroke through ≥24 months and 24-month new brain infarction on T2 MRI. Median 3.2-year follow-up. Published NEJM 2017.
ClinicalTrials.gov
NCT00738894Bedside Pearl
REDUCE: in patients 18–59 with cryptogenic stroke and PFO (with anticoagulation NOT permitted in the comparator), Gore HELEX/Cardioform closure + antiplatelet vs antiplatelet alone reduced recurrent clinical stroke from 5.4% to 1.4% over median 3.2y (HR 0.23, P=0.002, NNT ~28). Atrial fibrillation rose to 6.6%, largest AF signal of the three 2017 trials, but 83% within 45d, 59% resolved in 2 weeks. Read with CLOSE and RESPECT long-term.