Inclusion criteria
Patients (ages 18–60 years) with PFO who have a cryptogenic, ischemic stroke or imaging-confirmed TIA within 180 days prior to randomization
All patients must have MRI evidence of infarction or clinical symptoms persisting for ≥24 h
PFO determined by positive bubble study utilizing TEE
Either at rest or during Valsalva maneuver
Patient has no evidence of hypercoagulable state, which requires anticoagulation therapy
Subject provided informed consent to participate in the trial
Exclusion criteria
Conditions suggesting non-cryptogenic sources of stroke
Examples include:
Lacunar stroke syndrome
Large artery atherosclerosis with either ≥50 % stenosis or ulcerated plaque
Atrial fibrillation or flutter
Dilated cardiomyopathy
Uncontrolled diabetes mellitus or hypertension
Active autoimmune disease
Modified Rankin Scale ≥3
Anatomic contraindication to PFO closure with Helex or GSO
Sensitivity or contraindication preventing or hindering adherence to randomized therapy
Inability to comply with the study protocol, including follow-up visits
Upon completion of screening tests and confirmation of study eligibility, consented subjects are randomized to the treatment versus control arm in a 2:1 ratio. Subjects randomized to the test arm must be treated (PFO device closure) within 90 days of randomization. Investigators prescribe antiplatelet medical therapy regimens for all subjects, test and control, based on their best medical judgment using one of the three options listed below.
1.
Aspirin alone: Dosage between 75 and 325 mg once daily.
2.
Aggrenox™ or generic equivalent: Total daily dosage of 50–100 mg of aspirin and 225–400 mg of dipyridamole.
3.
Clopidogrel (Plavix®) or generic equivalent: Dosage of 75 mg once daily.
Investigators are strongly encouraged to use the same antiplatelet regimen for each individual patient regardless of randomization. All subjects are treated with one of these three antiplatelet medication options through 24 months or until the occurrence of a new-onset stroke or imaged confirmed TIA with MRI evidence of infarction, whichever occurs first. Subjects are encouraged to stay on their prescribed medication throughout the 5-year follow-up period. All subjects randomized to the test arm undergo percutaneous PFO device closure attempt with either Helex or GSO device shown in. In addition, the test arm subjects are also continued on antiplatelet medical therapy using one of the three regimens listed above.
Reduce Primary Endpoints
The primary endpoint for the REDUCE study is freedom from recurrent ischemic stroke or imaging-confirmed TIA through at least 24 months post-randomization. All deaths and suspected recurrent stroke or TIA events are reviewed and adjudicated by the blinded Clinical Events Committee. In the event of subject death, all possible efforts are made to obtain relevant records to determine the cause of death.
Reduce Secondary Endpoints
Safety endpoints include the proportion of subjects who experience adverse events determined to be related to device, procedure, and/or antiplatelet medical management. The efficacy endpoint is PFO closure success measured by assessing the degree of residual right-to-left shunt after device implant.
Additional Secondary Endpoints:
1.
Imaging: Change in MRI lesions from screening through 24 months or last follow-up visit, whichever occurs first.
2.
Time to any stroke/TIA and overall survival.
3.
Device Success: Device arm subjects with successful implant and retention of the Gore Helex Septal Occluder/Gore Septal Occluder.
4.
Device Arm Clinical Success: Composite of device success, PFO closure, and achievement of primary endpoint.
Summary
There have been three randomized trials [1–3] and multiple systematic reviews [4–6] that have reported results in recent years examining PFO closure to reduce the risk of recurrent stroke in cryptogenic stroke patients. REDUCE has design elements that allow it to contribute new information on the PFO-stroke question and overcome challenges experienced by these other studies. REDUCE, however, also faces certain obstacles that have challenged other PFO-stroke studies. The REDUCE trial employs eligibility criteria that optimize the enrollment of patients with embolic strokes with no alternative cause. REDUCE requires that all patients be treated with antiplatelet therapy, regardless of randomization, allowing for a consistent assessment of the effect of PFO closure without confounding by other interventions. REDUCE will compare MRIs at 24 months to baseline to detect subclinical or silent brain infarctions, providing additional data on the potential effects of PFO closure on ischemic brain injury. These elements of the REDUCE trial design hopefully will allow it to definitively determine if PFO closure is an effective strategy for reducing the risk of recurrent cerebral infarction.
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