STEM
Embolization of the Middle Meningeal Artery for Chronic Subdural Hematoma
Clinical Question
In patients with symptomatic chronic subdural hematoma, does adjunctive middle meningeal artery (MMA) embolization with the Squid liquid embolic agent reduce the risk of treatment failure compared with standard treatment alone?
Study Overview
Objective
To evaluate the effectiveness of SQUID MMA embolization in treating chronic subdural hematoma (SDH).
Study Summary
SQUID MMA embolization significantly reduced the primary outcome of residual, reaccumulation, re-operation, stroke, MI, or death in patients with symptomatic chronic SDH..
Intervention
Standard care (medical or surgical) +/- MMA embolization.
Patients per Arm
Not specified in given information
Bottom Line
Among patients with symptomatic chronic subdural hematoma, adjunctive MMA embolization with Squid significantly reduced the risk of treatment failure (a 180-day composite of residual/recurrent hematoma, reoperation or surgical rescue, and major disabling stroke, MI, or death from neurologic causes) compared with standard treatment alone, without increasing the short-term risk of disabling stroke or death.
Major Points
- STEM showed that adjunctive middle meningeal artery (MMA) embolization with the Squid liquid embolic agent reduces the risk of treatment failure among patients receiving standard treatment for chronic subdural hematoma, without an increased incidence of disabling stroke or death in the short term.
- Primary composite outcome (treatment failure at 180 days) occurred in 16% (19/120) with embolization vs 36% (47/129) with control (OR 0.36, 95% CI 0.20–0.66, p=0.001; NNT ~5).
- Safety was equivalent: the primary safety outcome (major disabling stroke or death from any cause at 30 days) occurred in 3% of both groups (4/144 embolization vs 5/166 control).
- The benefit was numerically larger in the nonsurgical stratum (OR 0.19, 95% CI 0.08–0.46; 19% vs 56%) than in the surgical stratum (OR 0.60, 95% CI 0.27–1.35; 14% vs 23%), though the trial was not powered for stratified comparisons.
- Used Squid (ethylene vinyl alcohol copolymer in DMSO, with tantalum for radiopacity) as the embolic agent — a nonadhesive liquid embolic.
- Enrolled 310 patients at 32 centers (Nov 2020–May 2023), with pre-randomization stratification by surgical vs nonsurgical standard treatment; the operator chose the standard treatment strategy before randomization to ± embolization.
- Reoperation or surgical rescue within 180 days — the dominant driver of the composite outcome — was substantially lower with embolization: 10% (12/120) vs 30% (39/129).
- All-cause mortality at 180 days was numerically higher in the embolization group (8% vs 5%; difference 2.9 percentage points, 95% CI −2.9 to 9.3; not statistically significant); death from neurologic causes was numerically lower with embolization (1% vs 2%).
- 40% of patients overall were on anticoagulants or antiplatelets at baseline (42% control, 38% embolization) — a real-world population in whom chronic SDH recurrence rates are highest.
Design
Study Type: Prospective, international, multicenter, open-label, interventional, randomized, controlled trial (investigational device exemption).
Randomization: 1
Blinding: Open-label for treatment assignment. Imaging core-laboratory adjudication could not be blinded due to the radiopacity of the Squid embolic agent. An independent clinical events committee adjudicated potential clinical primary-outcome events, neurologic serious adverse events, and deaths.
Enrollment Period: November 2020 through May 2023.
Follow-up Duration: 180 days.
Centers: 32
Countries: United States, France (based on author affiliations; countries not explicitly enumerated in the paper)
Sample Size: 310
Analysis: Intention-to-treat (Cochran–Mantel–Haenszel test stratified by surgical vs nonsurgical standard treatment; multiple imputation for missing data with prespecified sensitivity/tipping-point analyses). Safety analyzed in the safety population by actual treatment received.
Inclusion Criteria
- Symptomatic chronic subdural hematoma measuring >10 mm in maximum thickness on imaging
- Hematoma considered chronic if ≥50% of the collection volume was iso- or hypodense relative to cortical gray matter
- Pre-symptom modified Rankin Scale score ≤1 (functionally independent at baseline)
- Target side (left, right, or both) determined before randomization; bilateral targets allowed only if all criteria met for both sides
Exclusion Criteria
- Pre-symptom modified Rankin Scale score >1
- Previous craniotomy for the current hematoma
- (Additional protocol exclusions detailed in the supplementary appendix/protocol)
Arms
| Field | Control | MMA Embolization + Standard Treatment |
|---|---|---|
| Intervention | Either surgical evacuation (burr-hole in the majority; SEPS drainage in some) or nonsurgical management, chosen by the treating surgeon before randomization. | Middle meningeal artery embolization with the Squid liquid embolic agent (ethylene vinyl alcohol copolymer in DMSO with tantalum), performed within 24 hours of randomization (before surgical evacuation in the surgical stratum), as an adjunct to the pre-selected standard treatment. |
| Duration | 180 days follow-up | 180 days follow-up |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Composite of treatment failure at 180 days: recurrent or residual chronic SDH >10 mm on the target side at 180 days; reoperation or surgical rescue within 180 days; or major disabling stroke, MI, or death from neurologic causes within 180 days. | Primary | 36% (47/129) | 16% (19/120) | ~20 percentage points | 0.001 |
| Modified Rankin Scale score at 180 days | Secondary | 0.65 (not significant) | |||
| Primary safety outcome (major disabling stroke or death from any cause within 30 days) | Adverse | 3% (5/166) | 3% (4/144) | Difference 0.2 percentage points (exact 95% CI −4.5 to 4.4) | |
| Death from any cause at 180 days | Adverse | 5% (9 patients) | 8% (12 patients) | Difference 2.9 percentage points (exact 95% CI −2.9 to 9.3) | |
| Death from neurologic causes at 180 days | Adverse | 2% (3 patients) | 1% (1 patient) | ||
| Major disabling stroke through 180 days | Adverse | 1% (2 patients) | 1% (2 patients) | Difference 0.2 percentage points (exact 95% CI −3.2 to 3.9) |
Criticisms
- Data were missing for 15% of the intention-to-treat population (13% of the modified ITT population), plausibly related to the older population and the COVID-19 pandemic; multiple imputation and tipping-point sensitivity analyses were performed but residual bias cannot be ruled out.
- Reoperation/surgical rescue — the dominant driver of the composite primary outcome — was decided by unblinded operators, introducing potential bias, although 80% of surgical rescues had documented imaging deterioration.
- Imaging core-laboratory adjudication could not be blinded due to the radiopacity of the Squid embolic agent.
- The trial was not powered to compare the surgical and nonsurgical strata; stratum-specific analyses were not part of a prespecified hierarchical plan and were not adjusted for multiplicity.
- All-cause mortality at 180 days was numerically higher in the embolization group (8% vs 5%), warranting further study of longer-term safety.
- The sponsor (Balt USA) manufactured the injected agent and assisted with statistical analysis and data preparation for publication, although the principal investigators wrote the first manuscript draft without sponsor input.
Funding
Balt USA
Based on: STEM (The New England Journal of Medicine, 2025)
Authors: David Fiorella, M.D., Ph.D., ..., M.P.H.
Citation: N Engl J Med 2025;392:855-64.
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