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FRED

Safety and Efficacy Results of the Flow Redirection Endoluminal Device (FRED) Stent System in the Treatment of Intracranial Aneurysms: US Pivotal Trial

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Year of Publication: 2022

Authors: Cameron G McDougall, Orlando Diaz, Alan Boulos, ..., Christopher F Dowd

Journal: Journal of NeuroInterventional Surgery

Citation: J NeuroIntervent Surg. 2022;14:577-584.

Link: https://doi.org/10.1136/neurintsurg-2021-017469

PDF: https://jnis.bmj.com/content/neurintsurg...017469.full.pdf

Clinical Question

Does the FRED flow diverter meet FDA-specified performance goals for safety and effectiveness in endovascular treatment of intracranial aneurysms with unfavorable morphology?

Bottom Line

The FRED flow diverter met both FDA performance goals: primary safety endpoint (death/major stroke ≤30 days or major ipsilateral stroke/neurological death ≤1 year) was 6.2% (9/145), well below the <15% threshold. Complete aneurysm occlusion with ≤50% stenosis and no retreatment at 12 months was 57.6% (80/139), exceeding the >46% goal. Disabling/fatal neurological events occurred in only 2.8% (4/145).

        Major Points
        Primary safety met: 9/145 (6.2%) composite safety events, below <15% performance goal (posterior probability 0.999).
Low disabling morbidity/mortality: only 4/145 (2.8%) experienced disabling stroke (mRS >2) or death.
Primary effectiveness exceeded goal: 80/139 (57.6%) composite endpoint (complete occlusion + no significant stenosis (≤50%) + no retreatment) at 12 months, above >46% threshold.
Alternative composite endpoint (near-complete 90-100% occlusion + no significant stenosis + no retreatment): 100/139 (71.9%). Aneurysm occlusion 90% or greater alone: 112/140 (80.0%). Complete Raymond 1 alone: 88/140 (62.9%).
Predominantly large/giant aneurysms: 73.1% were >10mm (core lab); mean dome height 11.5mm.
Single-device treatment in 93.1% (vs Pipeline PUFS median 3 devices).
Device thrombosis 8.3% (12/145) — all 8 periprocedural events resolved with IIb/IIIa inhibitors.
PComA location had disproportionate stroke risk: 5/6 major strokes within 30 days (P<0.001).
Parent artery stenosis ≥50%: only 4.3% (6/139) at 12 months.
Retreatment rate 5.7% (8/140) within 12 months; device migration/foreshortening in ≥3 failures.

      

Design

Study Type: Prospective, multicenter, single-arm, investigational device exemption (IDE) pivotal trial

Randomization:

Blinding: Independent blinded Clinical Events Committee; independent blinded DSMB; independent angiographic core laboratory.

Enrollment Period: July 2013 to December 2016

Follow-up Duration: 12 months (clinical at 30d, 90d, 180d, 1yr; angiographic at 180d and 1yr)

Centers: 23

Countries: United States, Japan

Sample Size: 145

Analysis: Bayesian; 95% credible intervals; non-inferiority vs performance goals (safety <15%, effectiveness >46%).

Inclusion Criteria

Intracranial aneurysm with unfavorable morphology for traditional endovascular therapies (large, wide-necked, fusiform).
Target aneurysm proximal to AComA segment, MCA M1/M2 junction, or basilar bifurcation.
Parent artery diameter 2.0-5.0 mm.
Wide-necked or morphologically unsuitable for standard coiling.
Written informed consent.

Exclusion Criteria

Recent SAH within <60 days.
Proximal arterial stenosis >50%.
Dolichoectatic aneurysms.
Bifurcation aneurysms.
Prior stenting of the target aneurysm.
Atrial fibrillation.

Baseline Characteristics

All Patients (N=145):

Age (mean±SD): 59.1±11.5
Female sex: 129 (89%)
White race: 104 (71.7%)
Hypertension: 90 (62.1%)
Hyperlipidemia: 64 (44.1%)
Diabetes: 14 (9.7%)
Prior stroke: 5 (3.4%)
Multiple aneurysms: 36 (24.8%)
Tobacco use: 48 (33.1%)
mRS 0: 103 (71.0%)
mRS 1: 31 (21.4%)
Aneurysm location — Ophthalmic: 50 (34.5%)
Aneurysm location — Cavernous carotid: 41 (28.3%)
Aneurysm location — PComA: 20 (13.8%)
Mean dome height (±SD): 11.5±4.7 mm
Large (>10mm) by core lab: 106 (73.1%)
Previously treated (clips/coils): 25 (17.2%)

Arms

Field	FRED Flow Diverter (single arm)
Intervention	Self-expanding nitinol flow diverter with dual-layer design (inner 36 or 48 wire low-porosity braid). Available diameters 2.5-5.5mm, working length 7-39mm. Delivered via Headway 21 (≤3mm) or Headway 27 (>3mm) microcatheter. DAPT (aspirin + clopidogrel) loading pre-procedure, maintained ≥6 months then monotherapy. Single device in 93.1%.
Duration	Single procedure + 12-month follow-up

Outcomes

Outcome	Type	Control	Intervention	P-value
Safety: death/major stroke ≤30 days or major ipsilateral stroke/neurological death ≤12 months. Effectiveness: complete occlusion (Raymond 1) + ≤50% parent artery stenosis + no retreatment at 12 months.	Primary	Performance goals: safety <15%, effectiveness >46%	Safety: 9/145 (6.2%). Effectiveness: 80/139 (57.6%).	Not applicable — Bayesian analysis. Posterior probability 0.999 (safety) and 0.997 (effectiveness), both exceeding 0.975 threshold.
Near-complete (90-100%) occlusion + ≤50% stenosis + no retreatment (alternative composite)	Secondary		100/139 (71.9%)
Aneurysm occlusion 90% or greater alone at 12 months	Secondary		112/140 (80.0%)
Complete occlusion (Raymond 1) at 12 months	Secondary		88/140 (62.9%)
No retreatment within 12 months	Secondary		132/140 (94.3%)
Parent artery stenosis ≥50% at 12 months	Secondary		6/139 (4.3%)
Major stroke at 12 months	Secondary		9/145 (6.2%)
Minor stroke at 12 months	Secondary		9/145 (6.2%)
mRS worsening at 180 days vs baseline	Secondary		19/137 (13.9%)
mRS worsening at 12 months vs baseline	Secondary		16/135 (11.9%)
FRED procedure-related serious adverse events	Secondary		40/145 (27.6%)
FRED device-related serious adverse events	Secondary		27/145 (18.6%)
Unsuccessful delivery of the FRED	Secondary		2/145 (1.4%)
Unsuccessful deployment of the FRED	Secondary		4/145 (2.8%)
Migration of the FRED implant at 12 months	Secondary		4/145 (2.8%)
Major stroke ≤30 days	Adverse		6/145 (4.1%)
Death ≤30 days	Adverse		0/145 (0%)
Major ipsilateral stroke 31-425 days	Adverse		3/145 (2.1%)
Neurological death 31-425 days	Adverse		1/145 (0.7%)
Device thrombosis	Adverse		12/145 (8.3%): 8 periprocedural (all resolved), 4 delayed
Aneurysm rupture	Adverse		2/145 (1.4%): both SAH, both recovered to mRS 0
Device-related SAEs (CEC-adjudicated)	Adverse		9/145 (6.2%): 6 strokes, 1 rupture, 2 TIAs
PComA location strokes	Adverse		5/6 major strokes ≤30d were PComA (P<0.001)

Subgroup Analysis

PComA location had disproportionate stroke risk: 5/9 primary safety events were PComA (P<0.005). No significant differences by site volume, gender, aneurysm size, anterior vs posterior circulation, or age.

Criticisms

No control group — single-arm with historically derived performance goals (paper explicitly notes 'lack of a control group' as the chief limitation).
Performance goals developed by sponsor (Microvention) with FDA — potential selection bias in literature chosen.
PComA clustering of major strokes unexplained — no device-specific mechanism identified.
Protocol violation: 1 patient with AF enrolled (exclusion criterion) — resulted in neurological death.
12-month follow-up only — flow diverter occlusion rates increase beyond 1 year.
Antiplatelet testing not required — clopidogrel resistance not evaluated.
Industry funded (Microvention-Terumo); multiple authors are consultants.

Funding

Microvention-Terumo Inc.

Based on: FRED (Journal of NeuroInterventional Surgery, 2022)

Authors: Cameron G McDougall, Orlando Diaz, Alan Boulos, ..., Christopher F Dowd

Citation: J NeuroIntervent Surg. 2022;14:577-584.

Content summarized and formatted by NeuroTrials.ai.

FRED

(2022)

Objective

To evaluate the safety and effectiveness of the Flow Redirection Endoluminal Device (FRED) flow diverter for intracranial aneurysms in support of FDA approval in the USA.

Study Summary

• The FRED flow diverter met FDA performance goals for both safety (<15%) and effectiveness (>46%), with a 6.2% composite safety event rate and 57.6% composite primary effectiveness (complete occlusion with ≤50% parent-artery stenosis and no retreatment) at 12 months; complete Raymond 1 occlusion alone was 62.9%.

Intervention

Single-arm treatment with the FRED dual-layer nitinol flow diverter, with clinical follow-up at 30d/90d/180d/1y and mandatory angiographic follow-up at 180 days and 12 months.

Inclusion Criteria

Adults with intracranial aneurysms of unfavorable morphology for traditional endovascular therapies (large, wide-necked, fusiform, etc); target aneurysm proximal to the AComA segment, MCA M1/M2 junction, or basilar bifurcation; parent artery diameter 2.0–5.0 mm.

Study Design

Arms: Single-arm trial using FRED device.

Patients per Arm: FRED: 167 consented; 145 underwent attempted treatment and had ≥1 FRED device implanted (ITT/safety population); 143/145 had 30-day follow-up; 139/145 had angiographic follow-up interpretable by core laboratory (180-day carried forward for 9 patients); 130/145 had 12-month angiography.

Outcome

• Primary Effectiveness Endpoint: Complete aneurysm occlusion at 12 months with ≤50% parent-artery stenosis and no retreatment achieved in 57.6% (80/139); • Primary Safety Endpoint: Major stroke/death within 30 days or major ipsilateral stroke/neurological death within 12 months occurred in 6.2% (9/145); • Disabling stroke (mRS >2) or neurological death: 2.8% (4/145); • Device thrombosis: 8.3% (12/145) — 8 periprocedural (all resolved) and 4 delayed; • Device implantation successful in all 145 patients (single device in 93.1%).

Bottom Line

Major Points

Primary safety met: 9/145 (6.2%) composite safety events, below <15% performance goal (posterior probability 0.999).
Low disabling morbidity/mortality: only 4/145 (2.8%) experienced disabling stroke (mRS >2) or death.
Primary effectiveness exceeded goal: 80/139 (57.6%) composite endpoint (complete occlusion + no significant stenosis (≤50%) + no retreatment) at 12 months, above >46% threshold.
Alternative composite endpoint (near-complete 90-100% occlusion + no significant stenosis + no retreatment): 100/139 (71.9%). Aneurysm occlusion 90% or greater alone: 112/140 (80.0%). Complete Raymond 1 alone: 88/140 (62.9%).
Predominantly large/giant aneurysms: 73.1% were >10mm (core lab); mean dome height 11.5mm.
Single-device treatment in 93.1% (vs Pipeline PUFS median 3 devices).
Device thrombosis 8.3% (12/145) — all 8 periprocedural events resolved with IIb/IIIa inhibitors.
PComA location had disproportionate stroke risk: 5/6 major strokes within 30 days (P<0.001).
Parent artery stenosis ≥50%: only 4.3% (6/139) at 12 months.
Retreatment rate 5.7% (8/140) within 12 months; device migration/foreshortening in ≥3 failures.

Study Design

Study Type: Prospective, multicenter, single-arm, investigational device exemption (IDE) pivotal trial
Randomization: No
Blinding: Independent blinded Clinical Events Committee; independent blinded DSMB; independent angiographic core laboratory.
Sample Size: 145
Follow-up: 12 months (clinical at 30d, 90d, 180d, 1yr; angiographic at 180d and 1yr)
Centers: 23
Countries: United States, Japan

Primary Outcome

Definition: Safety: death/major stroke ≤30 days or major ipsilateral stroke/neurological death ≤12 months. Effectiveness: complete occlusion (Raymond 1) + ≤50% parent artery stenosis + no retreatment at 12 months.

Control	Intervention	HR/OR	P-value
Performance goals: safety <15%, effectiveness >46%	Safety: 9/145 (6.2%). Effectiveness: 80/139 (57.6%).	- (Safety: 3.3-11.3%. Effectiveness: 49.2-65.5%.)	Not applicable — Bayesian analysis. Posterior probability 0.999 (safety) and 0.997 (effectiveness), both exceeding 0.975 threshold.

Limitations & Criticisms

No control group — single-arm with historically derived performance goals (paper explicitly notes 'lack of a control group' as the chief limitation).
Performance goals developed by sponsor (Microvention) with FDA — potential selection bias in literature chosen.
PComA clustering of major strokes unexplained — no device-specific mechanism identified.
Protocol violation: 1 patient with AF enrolled (exclusion criterion) — resulted in neurological death.
12-month follow-up only — flow diverter occlusion rates increase beyond 1 year.
Antiplatelet testing not required — clopidogrel resistance not evaluated.
Industry funded (Microvention-Terumo); multiple authors are consultants.

Citation

J NeuroIntervent Surg. 2022;14:577-584.

View Original Publication →

FRED

Safety and Efficacy Results of the Flow Redirection Endoluminal Device (FRED) Stent System in the Treatment of Intracranial Aneurysms: US Pivotal Trial

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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