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GORE-REDUCE

Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke

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Year of Publication: 2017

Authors: Lars Søndergaard, Scott E. Kasner, John F. Rhodes, ..., for the Gore REDUCE Clinical Study Investigators

Journal: New England Journal of Medicine

Citation: N Engl J Med 2017;377:1033-42

Link: https://doi.org/10.1056/NEJMoa1707404

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa1707404

Clinical Question

Does PFO closure combined with antiplatelet therapy reduce recurrent stroke and new brain infarctions compared to antiplatelet therapy alone in patients with cryptogenic stroke and PFO?

Bottom Line

Among patients with PFO and cryptogenic stroke, PFO closure plus antiplatelet therapy significantly reduced recurrent ischemic stroke (1.4% vs 5.4%, HR 0.23, p=0.002) and new brain infarctions (4.7% vs 10.7%, p=0.02) compared to antiplatelet therapy alone, though closure was associated with increased atrial fibrillation (6.6% vs 0.4%).

        Major Points
        First PFO closure trial mandating antiplatelet-only therapy in both arms (no anticoagulation allowed)
2:1 randomization: 441 patients to PFO closure + antiplatelet vs 223 to antiplatelet alone
Two coprimary endpoints: clinical stroke and composite of clinical stroke or silent brain infarction
81% of patients had moderate or large interatrial shunts at baseline
Median follow-up 3.2 years (range 2-5 years)
Clinical stroke significantly reduced: 1.4% vs 5.4% (HR 0.23, 95% CI 0.09-0.62, p=0.002)
New brain infarction reduced: 4.7% vs 10.7% (RR 0.44, 95% CI 0.24-0.81, p=0.02)
Silent brain infarction alone showed no difference: 3.4% vs 4.0% (p=0.75)
NNT = 28 patients to prevent 1 stroke at 24 months
Complete PFO closure achieved in 75.6% at 12 months; effective closure in 94.5%
Atrial fibrillation significantly higher with closure (6.6% vs 0.4%, p<0.001), but 83% occurred within 45 days and 59% resolved within 2 weeks
Used GORE HELEX (through 2012) and CARDIOFORM (from 2012 onward) devices
Statistical plan modified mid-trial: neuroimaging endpoint elevated from secondary to coprimary after enrollment of 467 patients

      

Design

Study Type: Multinational, prospective, randomized, controlled, open-label trial with blinded adjudication

Randomization: 1

Blinding: Open-label treatment assignment; blinded clinical events committee and MRI core laboratory for outcome adjudication

Enrollment Period: December 2008 to February 2015

Follow-up Duration: Median 3.2 years (IQR 2.2-4.8); minimum 2 years, maximum 5 years

Centers: 63

Countries: Canada, Denmark, Finland, Norway, Sweden, United Kingdom, United States

Sample Size: 664

Analysis: Intention-to-treat for primary analysis; Log-rank test for time-to-event (clinical stroke); Two-sample binomial test for brain infarction composite; Kaplan-Meier survival curves; P-values adjusted for multiplicity using Dubey and Armitage-Parmar procedure; Per-protocol and as-treated sensitivity analyses performed

Inclusion Criteria

Age 18-59 years
Cryptogenic ischemic stroke within 180 days before randomization
Focal neurologic deficit lasting ≥24 hours OR <24 hours with MRI/CT evidence of infarction
PFO with right-to-left shunt on transesophageal echocardiography with agitated saline (at rest or during Valsalva)
Comprehensive workup ruling out other stroke mechanisms: no large-artery disease (≥50% stenosis or occlusion), no lacunar stroke, no cardioembolic source, no hypercoagulable disorder requiring anticoagulation, no arterial dissection

Exclusion Criteria

Age ≥60 years
Large-artery atherosclerotic disease (≥50% stenosis or vessel occlusion on CTA/MRA/ultrasound/catheter angiography)
Small-vessel occlusive disease (lacunar stroke: <1.5cm deep infarction or typical lacunar syndrome)
Established cardioembolic source
Specific indication for anticoagulation
Hypercoagulable disorder requiring anticoagulation
Arterial dissection
Uncontrolled diabetes mellitus
Uncontrolled hypertension
Autoimmune disease
Recent history of alcohol or drug abuse

Baseline Characteristics

Characteristic	Control	Active
N	223	441
Age (years)	44.8 ± 9.6	45.4 ± 9.3
Days from stroke to randomization	101 ± 53	100 ± 52
Male sex	61.9%	59.2%
Current smoking	11.2%	14.3%
Hypertension	26.0%	25.4%
Diabetes	4.5%	4.1%
Previous stroke or TIA	10.3%	14.1%
Previous stroke	5.8%	9.5%
Previous TIA	4.9%	5.9%
Stroke symptoms ≥24 hours	89.2%	91.2%
Stroke symptoms <24 hours with imaging	10.8%	8.8%
Small shunt	19.9%	18.1%
Moderate shunt	43.5%	39.1%
Large shunt	36.6%	42.8%
Atrial septal aneurysm	Not assessed (determined only at time of closure procedure)	20.4%

Arms

Field	Control	PFO Closure + Antiplatelet Therapy
Intervention	Antiplatelet therapy chosen by investigator (uniform within each site): aspirin 75-325mg daily alone, OR aspirin 50-100mg + dipyridamole 225-400mg daily, OR clopidogrel 75mg daily. Continued for duration of trial.	Transcatheter PFO closure within 90 days using GORE HELEX Septal Occluder (through late 2012) or CARDIOFORM Septal Occluder (from late 2012 onward). Loading dose clopidogrel 300mg before/after procedure if not already on it, then 75mg daily for 3 days, then resume chosen antiplatelet regimen (same options as control). Median 28 days from randomization to procedure.
Duration	Minimum 2 years, median 3.2 years	Minimum 2 years, median 3.2 years

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Coprimary endpoint 1: Freedom from clinical ischemic stroke through ≥24 months (reported as recurrent stroke rate)	Primary	12/223 (5.4%); 1.71 per 100 patient-years	6/441 (1.4%); 0.39 per 100 patient-years	0.23	0.002
Coprimary endpoint 2: New brain infarction at 24 months (composite of clinical stroke or silent infarct ≥3mm on T2/FLAIR MRI)	Secondary	19/177 (10.7%) with available MRI	18/383 (4.7%) with available MRI	RR 0.44 (95% CI 0.24-0.81); Absolute difference 6.0% (95% CI 1.0-11.1)	0.02
Recurrent clinical ischemic stroke (component of coprimary 2)	Secondary	12/177 (6.8%)	5/383 (1.3%)	RR 0.19 (95% CI 0.07-0.54)	0.005
Silent brain infarction only (component of coprimary 2)	Secondary	7/177 (4.0%)	13/383 (3.4%)	RR 0.86 (95% CI 0.35-2.11)	0.75
Successful device implantation and retention	Secondary	N/A	408/413 attempted (98.8%); 158 HELEX, 250 CARDIOFORM
Complete PFO closure immediately post-procedure	Secondary	N/A	73.2%
Complete PFO closure at 12 months	Secondary	N/A	75.6%
Effective closure (freedom from large shunt) at 12 months	Secondary	N/A	94.5%
Any serious adverse event	Adverse	62/223 (27.8%)	102/441 (23.1%)		0.22
Death	Adverse	0	2/441 (0.5%): 1 suicide at 131 days, 1 MI at 1045 days		0.55
Any atrial fibrillation or flutter	Adverse	1/223 (0.4%)	29/441 (6.6%); 83% within 45 days, 59% resolved within 2 weeks		<0.001
Serious atrial fibrillation or flutter	Adverse	1/223 (0.4%)	10/441 (2.3%)		0.11
Device-related serious adverse events	Adverse	N/A	6/441 (1.4%): 3 device dislocation, 2 device thrombosis, 1 aortic dissection
Procedure-related serious adverse events	Adverse	N/A	11/441 (2.5%)
Serious bleeding adverse event	Adverse	6/223 (2.7%)	8/441 (1.8%); 4 procedure-associated (3 vascular access, 1 tamponade)		0.57
Deep-vein thrombosis or pulmonary embolism	Adverse	2/223 (0.9%)	3/441 (0.7%)		1.00

Subgroup Analysis

Subgroup analyses by age (18-45 vs 46-59), sex, region (Europe/Canada vs US), and shunt size (small vs moderate-to-large) showed no significant interactions. Treatment effect favoring PFO closure was consistent across all subgroups: Age 18-45: HR 0.26 (p=0.04); Age 46-59: HR 0.21 (p=0.02); Male: HR 0.19 (p=0.01); Female: HR 0.31 (p=0.11); Europe/Canada: HR 0.23 (p=0.03); US: HR 0.24 (p=0.03); Small shunt: HR 0.27 (p=0.26); Moderate-to-large shunt: HR 0.18 (p=0.001). No interaction P-values were significant.

Criticisms

Open-label design increases risk of ascertainment bias despite blinded outcome adjudication
Differential dropout: 8.8% in closure group vs 14.8% in antiplatelet group discontinued trial
Crossover issues: 14 patients (6.3%) in antiplatelet group underwent closure outside trial; 28 patients (6.3%) assigned to closure never attempted device implantation
Statistical plan changed mid-trial: neuroimaging endpoint elevated from secondary to coprimary after 467 patients enrolled due to lower-than-expected event rates in other PFO trials
Silent infarcts not reduced despite reduction in clinical strokes - raises possibility of referral bias in open-label setting
No requirement for Holter or prolonged cardiac monitoring to exclude paroxysmal atrial fibrillation
MRI detection threshold (≥3mm T2/FLAIR lesions) may be insensitive for smaller silent infarcts
Higher than expected stroke rate in antiplatelet arm compared to previous trials
Relatively low total event rate limits subgroup analysis power
Atrial fibrillation significantly increased with closure - long-term stroke implications unclear
Younger, carefully selected population (age <60, strict cryptogenic criteria, controlled risk factors) may limit generalizability
Missing follow-up MRI data in 7.5% overall (6.6% closure, 9.4% antiplatelet)
Two different devices used (HELEX vs CARDIOFORM) though outcomes were similar
Median time from stroke to randomization was 102 days - relatively long interval

Funding

W.L. Gore and Associates (device manufacturer and sponsor)

Based on: GORE-REDUCE (New England Journal of Medicine, 2017)

Authors: Lars Søndergaard, Scott E. Kasner, John F. Rhodes, ..., for the Gore REDUCE Clinical Study Investigators

Citation: N Engl J Med 2017;377:1033-42

Content summarized and formatted by NeuroTrials.ai.

GORE-REDUCE

(2017)

Objective

PFO closure plus antiplatelet therapy versus antiplatelet therapy alone in patients with cryptogenic stroke and right-to-left shunt.

Study Summary

• PFO closure combined with antiplatelet therapy was associated with a lower risk of recurrent ischemic stroke compared to antiplatelet therapy alone.

Intervention

PFO closure with HELEX Septal Occluder or Cardioform Septal Occluder plus antiplatelet therapy vs. antiplatelet therapy alone.

Inclusion Criteria

Patients aged 18-59 with cryptogenic stroke within 180 days and PFO with right-to-left shunt confirmed by TEE.

Study Design

Arms: PFO Closure plus Antiplatelet Therapy vs. Antiplatelet Therapy Alone

Patients per Arm: PFO Closure: 441, Antiplatelet Therapy: 223

Outcome

• Reduction in recurrent ischemic stroke with PFO closure compared to antiplatelet therapy alone. <br>• Recurrent stroke: 1.4% vs 5.4% (HR 0.23, p=0.002)
• New brain infarction: 4.7% vs 10.7% (p=0.02)
• Atrial fibrillation: 6.6% vs 0.4% (p<0.001)

Bottom Line

Major Points

First PFO closure trial mandating antiplatelet-only therapy in both arms (no anticoagulation allowed)
2:1 randomization: 441 patients to PFO closure + antiplatelet vs 223 to antiplatelet alone
Two coprimary endpoints: clinical stroke and composite of clinical stroke or silent brain infarction
81% of patients had moderate or large interatrial shunts at baseline
Median follow-up 3.2 years (range 2-5 years)
Clinical stroke significantly reduced: 1.4% vs 5.4% (HR 0.23, 95% CI 0.09-0.62, p=0.002)
New brain infarction reduced: 4.7% vs 10.7% (RR 0.44, 95% CI 0.24-0.81, p=0.02)
Silent brain infarction alone showed no difference: 3.4% vs 4.0% (p=0.75)
NNT = 28 patients to prevent 1 stroke at 24 months
Complete PFO closure achieved in 75.6% at 12 months; effective closure in 94.5%
Atrial fibrillation significantly higher with closure (6.6% vs 0.4%, p<0.001), but 83% occurred within 45 days and 59% resolved within 2 weeks
Used GORE HELEX (through 2012) and CARDIOFORM (from 2012 onward) devices
Statistical plan modified mid-trial: neuroimaging endpoint elevated from secondary to coprimary after enrollment of 467 patients

Study Design

Study Type: Multinational, prospective, randomized, controlled, open-label trial with blinded adjudication
Randomization: Yes
Blinding: Open-label treatment assignment; blinded clinical events committee and MRI core laboratory for outcome adjudication
Sample Size: 664
Follow-up: Median 3.2 years (IQR 2.2-4.8); minimum 2 years, maximum 5 years
Centers: 63
Countries: Canada, Denmark, Finland, Norway, Sweden, United Kingdom, United States

Primary Outcome

Definition: Coprimary endpoint 1: Freedom from clinical ischemic stroke through ≥24 months (reported as recurrent stroke rate)

Control	Intervention	HR/OR	P-value
12/223 (5.4%); 1.71 per 100 patient-years	6/441 (1.4%); 0.39 per 100 patient-years	0.23 (0.09-0.62)	0.002

Limitations & Criticisms

Open-label design increases risk of ascertainment bias despite blinded outcome adjudication
Differential dropout: 8.8% in closure group vs 14.8% in antiplatelet group discontinued trial
Crossover issues: 14 patients (6.3%) in antiplatelet group underwent closure outside trial; 28 patients (6.3%) assigned to closure never attempted device implantation
Statistical plan changed mid-trial: neuroimaging endpoint elevated from secondary to coprimary after 467 patients enrolled due to lower-than-expected event rates in other PFO trials
Silent infarcts not reduced despite reduction in clinical strokes - raises possibility of referral bias in open-label setting
No requirement for Holter or prolonged cardiac monitoring to exclude paroxysmal atrial fibrillation
MRI detection threshold (≥3mm T2/FLAIR lesions) may be insensitive for smaller silent infarcts
Higher than expected stroke rate in antiplatelet arm compared to previous trials
Relatively low total event rate limits subgroup analysis power
Atrial fibrillation significantly increased with closure - long-term stroke implications unclear
Younger, carefully selected population (age <60, strict cryptogenic criteria, controlled risk factors) may limit generalizability
Missing follow-up MRI data in 7.5% overall (6.6% closure, 9.4% antiplatelet)
Two different devices used (HELEX vs CARDIOFORM) though outcomes were similar
Median time from stroke to randomization was 102 days - relatively long interval

Citation

N Engl J Med 2017;377:1033-42

View Original Publication →

GORE-REDUCE

Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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