Middle Meningeal Artery Embolization Does Not Confer Protection against Symptomatic Recurrence in Patients with Early Antithrombotic Therapy Following Surgery for Chronic Subdural Hematomas

Abstract

Objective: Middle meningeal artery embolization (MMAE) has emerged as a promising treatment, both as an adjunct to surgery and as a primary treatment for chronic subdural hematoma (cSDH). Here, we evaluate the efficacy of MMAE following surgery in reducing the likelihood of reoperation in patients requiring early introduction of antithrombotics.

Methods: From our prospectively collected registry of patients with cSDH, we identified patients treated with surgical evacuation, either in combination with or without MMAE. Patients were included if they had a clinical indication requiring early antithrombotics within 7 days of surgery. The primary outcome was the rate of reoperation. The secondary outcomes included recurrence in midline shift or changes in cSDH width based on imaging findings.

Results: Among 43 patients (53 total cSDHs) who met the inclusion criteria for the study, the median age was 71 years, 13% were female, the mean SDH thickness was 17.9 mm, and the most commonly used postoperative antithrombotic was aspirin. Sixteen cSDHs in 13 patients were treated with MMAE + surgery, while 37 cSDHs in 30 patients were treated with surgery alone. There was no difference in reoperation rates between the 2 groups (8.1% vs. 0%, surgery alone vs. surgery + MMAE, p = 0.55), nor in the rate of recurrence (24.3% vs. 12.5%, surgery alone vs. surgery + MMAE, p = 0.47).

Conclusion: In this single-center cohort study, we found no clear benefit in reduced rates of reoperation or recurrence for adjunctive MMAE in patients with cSDH treated with surgical evaluation. Despite this, encouraging trends were observed in the MMAE + surgery group.

Introduction

Chronic subdural hematoma (cSDH) is an increasingly prevalent condition that carries significant morbidity and mortality.¹⁾ This significant increase in mortality stems from the fact that 12-month mortality have been reported at 15%–20% as recently as 2022, with the highest reaching 32%. Also, cSDH has a large impact on survival, as patients with cSDH exhibit a higher long-term excess risk of mortality compared to the general population.²⁾ With the aging population steadily increasing, the incidence of cSDH is on the rise.³⁾ Standard treatment for cSDH has traditionally involved surgical evacuation.⁴⁾ Middle meningeal artery embolization (MMAE) has emerged as a promising treatment, both as an adjunct to surgery and as a primary therapy.⁵⁾ The efficacy of MMAE in treating cSDH has been recently demonstrated in large randomized trials and is currently being investigated in multiple clinical trials.⁶⁾

Clinical decision-making of antithrombotic medication (antiplatelet [AP] or anticoagulation) management is commonly encountered in patients with cSDH.^7–9) The use of antithrombotics, particularly anticoagulants (ACs), has been implicated in both the development of cSDH and its recurrence following surgical treatment.^10,11) Despite this, patient comorbidities may necessitate the early recommencement of antithrombotics following surgery. Furthermore, among patients who underwent MMAE, those with early antithrombotic use demonstrated a higher rate of hematoma recurrence.¹²⁾ MMAE has thus been utilized as an adjunct to surgical interventions, particularly in patients requiring early initiation of antithrombotics. While it is thought to be potentially protective against recurrences in this patient population, supporting data remains limited.

The objective of this study was to evaluate whether the addition of MMAE to surgery for cSDH reduces the risk of recurrence in patients requiring early resumption of antithrombotic medication.

Materials and Methods

Study design

This is a single-center, retrospective cohort study of patients with cSDH treated at a Level 1 Academic Trauma Center. The study was approved by the local Institutional Review Board at McGovern Medical School (HSC-MS-21-0792), which waived the need for consent. All consecutive cases of patients who underwent surgery for cSDH between January 1, 2016, and December 31, 2017, were eligible for inclusion in the historical surgery cohort. Additionally, all consecutive cases from a prospectively collected MMAE registry between 2018 and January 2023 were eligible for inclusion in the surgery + MMAE cohort. Starting in 2018, all patients with cSDH at our institution were evaluated by our neuro-endovascular team for MMAE and underwent the procedure unless any anatomical or medical restrictions were present.

Patients were eligible for inclusion if they had 1) surgical evacuation of cSDH using either burr holes or craniotomy, 2) radiological follow-up between 1 week and 6 months, and 3) commencement of antithrombotic within 1 week of surgery. Antithrombotic therapy was defined as the initiation of any AP or AC agent at therapeutic doses (not prophylactic). This included both the resumption of prior antithrombotic therapy and new initiations.

All MMAE cases were performed under general anesthesia. Transfemoral access was utilized with a 6F sheath. A 6F guide catheter was navigated to the proximal external carotid artery. Subsequently, a microcatheter system was navigated to access the middle meningeal artery, and a microcatheter run was performed to confirm placement. Embolization was then performed. Table 1 describes the different embolic materials used. The choice of embolic material was at the discretion of the treating physician; however, an attempt was made to proceed with distal access and liquid embolic embolization first. If this was not possible, particle treatment was attempted, followed by coil placement in the proximal MMA.

Table 1 Baseline characteristics by treatment group

	Total (n = 43)	Surgery (n = 30)	Surgery + MMAE (n = 13)	p-value
Age (years), median (IQR)	71 (64–76)	72 (64–76)	65 (64–74)	0.36
Female sex, n (%)	13 (30.2)	7 (23.3)	6 (46.2)	0.16
Bilateral lesions, n (%)	10 (23.3)	7 (23.3)	3 (23.1)	1
Evacuation, n (%)
Burr holes	28 (65.1)	21 (70.0)	7 (53.8)	0.32
Craniotomy	16 (37.2)	9 (30.0)	7 (53.8)	0.18
Embolization material, n (%)
Particles	—	—	8 (61.5)	—
Coils	—	—	7 (53.8)	—
Liquid embolic	—	—	5 (38.5)	—
Pre-antiplatelet agents, n (%)	29 (67.4)	23 (76.7)	6 (46.2)	0.077
Aspirin	27 (62.8)	21 (70.0)	6 (46.2)	0.18
Clopidogrel	12 (27.9)	10 (33.3)	2 (15.4)	0.29
Pre-anticoagulants, n (%)	18 (41.9)	11 (36.7)	7 (53.8)	0.33
Heparin	6 (14.0)	4 (13.3)	2 (15.4)	1
Warfarin	15 (34.9)	9 (30.0)	6 (46.2)	0.32
DOAC	2 (4.7)	1 (3.3)	1 (7.7)	0.52
Post-antiplatelet agents, n (%)	28 (65.1)	20 (66.7)	8 (61.5)	0.74
Aspirin	24 (55.8)	16 (53.3)	8 (61.5)	0.74
Clopidogrel	3 (7.0)	2 (6.7)	1 (7.7)	1
Post-op AP start (days), median (IQR)	4 (2–6)	5 (3–7)	2 (1.5–3.5)	0.028
Post-anticoagulant, n (%)	20 (46.5)	13 (43.3)	7 (53.8)	0.74
Heparin*	14 (32.6)	7 (23.3)	7 (53.8)	0.077
Warfarin*	15 (34.9)	9 (30.0)	6 (46.2)	0.32
DOAC	0 (0.0)	0 (0.0)	0 (0.0)
Post-op AC start (days), median (IQR)	1 (0–4)	1.5 (0–4.5)	5 (0–2.5)	0.29
Post-op AT start (days), median (IQR)	4 (1–6)	4.5 (3–6)	2 (0–4)	0.007

Data were analyzed using Student’s t-test for continuous variables and Fisher’s exact test for categorical variables.

*Some patients were on heparin bridge to warfarin. Sample size refers to patients rather than subdural hematoma.

AC, anticoagulant; AP, anti-platelet; AT, anti-thrombotic; DOAC, direct oral anticoagulant; IQR, interquartile range; MMAE, middle meningeal artery embolization

Outcome measures

The primary outcome was reoperation. Reoperation is pursued when there is an increase in lesion size accompanied by new or recurrent neurological deficits. The secondary outcomes were recurrence and changes in midline shift or the width of cSDHs. Recurrence was defined as reoperation, presence of acute blood, or enlargement of hematoma at follow-up.

Imaging analysis

CT imaging for each patient was assessed at 3 time points: immediately prior to surgery, postoperatively within 48 hours of surgery, and at follow-up. Follow-up time was defined as the interval between surgery and the follow-up. Postoperative imaging was used as a baseline for comparison with follow-up studies. The last available follow-up CT scan within the inclusion criteria was utilized. If multiple late follow-up CT scans were performed, the scan closest to 3 months after surgery was used. All imaging was assessed by a neurosurgeon (B.H.D.). On each CT scan, the maximal hematoma width was measured perpendicular to the skull on coronal images, and midline shift was measured at the level of the foramen of Monro.

Statistical analysis

Baseline characteristics were presented and analyzed on a per-patient basis. Clinical and radiographic outcomes were analyzed on a per-subdural basis. Descriptive statistics comparing the surgery and surgery + MMAE groups were performed using Student’s t-test for continuous variables and Fisher’s exact test for categorical variables. Recurrence- and reoperation-free survival curves were plotted using the Kaplan–Meier method, stratified by treatment group; a log-rank test was used to assess differences between survival curves. No imputation was performed for missing data points. Significance levels were set at p <0.05 for 2-tailed tests. All analyses were performed using STATA 17.0 (StataCorp, College Station, TX, USA).

Results

Baseline characteristics

A total of 37 cSDHs in 30 patients (surgery group) and 16 cSDHs in 13 patients (MMAE + surgery group) met the inclusion criteria (550 screened for the surgery group; 353 screened for the MMAE + surgery group). The median age was 72 (interquartile range [IQR] 64–76) in the surgery group and 65 (IQR 64–74) in the MMAE + surgery group, with no statistically significant difference. Females comprised 23.3% of the surgery group versus 46.2% in the MMAE + surgery group, but this difference did not reach statistical significance. The median time to antithrombotic restarting was significantly earlier in the MMAE + surgery group compared to surgery alone (2 vs. 4.5 days, p = 0.007). MMAE was performed prior to the initiation of antithrombotic therapy in all cases (median less than 2 days; all before day 4 of post-surgery). There was a higher use of AP agents in the surgery group at the time of presentation, which was not statistically significant (76.7% vs. 46.2%, p = 0.077).

In the surgery group, post-surgery AP use was 66.7% (20/30) versus 61.5% (8/13) in the MMAE + surgery group. The percentage of AC initiation was 43.3% (13/30) in the surgery group versus 53.8% (7/13) in the MMAE + surgery group. All restarted AC therapies were either heparin or warfarin; no direct oral ACs were used. Baseline demographics and imaging findings are summarized in Table 1.

Reoperation and radiological recurrence

There was no reoperation in the MMAE + surgery group versus 8.1% (3 reoperations) in the surgery-alone group. However, the rate of reoperation was not significantly different between the 2 cohorts (p = 0.55). Of the 9 expansions in the surgery group, 3 resulted in reoperation. None of the expansions in the surgery + MMAE group resulted in reoperation. The recurrence in the MMAE + surgery group was 12.5% (2 recurrences in 16 cSDHs), while in the surgery-alone group alone, it was 24.3% (9 recurrences in 37 cSDHs). This difference was not statistically different (Fig. 1). The median time to follow-up was 38 days for the surgery group versus 45.5 days for the MMAE + surgery (p = 0.14). At follow-up, the mean change in subdural width in the surgery and surgery + MMAE groups was −6.1 and −8.1 mm, respectively (p = 0.15). The change in midline shift in the surgery and surgery + MMAE groups was −2.9 and −3.9 mm, respectively (p = 0.19). Table 2 summarizes these findings.

Fig. 1 Kaplan-Meier curve for recurrence free survival in the 2 groups (Surgery versus Surgery + MMAE) showing no significant difference. MMAE, middle meningeal artery embolization

Table 2 Lesion characteristics and outcomes by treatment group

	Total (n = 53)	Surgery (n = 37)	Surgery + MMAE (n = 16)	p-value
Follow-up CT (days), median [IQR]	39.0 (20.0–61.0)	38.0 (17.0–59.0)	45.5 (26.5–65.0)	0.14
SDH thickness (mm), mean (SD)	17.9 (5.6)	17.7 (6.0)	18.2 (4.9)	0.79
Follow-up SDH thickness (mm), mean (SD)	6.9 (5.3)	7.7 (5.5)	5.0 (4.6)	0.09
Change in SDH thickness (mm), mean (SD)	−6.7 (4.8)	−6.1 (4.6)	−8.1 (5.1)	0.15
Recurrence, n (%)	11 (20.8)	9 (24.3)	2 (12.5)	0.47
Reoperation, n (%)	3 (5.7)	3 (8.1)	0 (0.0)	0.55
Midline shift (mm), mean (SD)	6.5 (3.7)	6.0 (3.6)	7.6 (3.8)	0.15
Follow-up midline shift (mm), mean (SD)	1.2 (1.8)	1.2 (1.9)	1.1 (1.5)	0.74
Change in midline shift (mm), mean (SD)	−3.2 (2.4)	−2.9 (2.4)	−3.9 (2.4)	0.19

IQR, interquartile range; MMAE, middle meningeal artery embolization; SD, standard deviation; SDH, subdural hematoma

Discussion

We report the first series analyzing the benefit of MMAE as an adjunct to surgery for cSDH in the setting of early initiation of antithrombotic medications. Within a limited sample, we found no clear benefit of MMAE in preventing cSDH recurrence after surgery in this patient population. However, although not reaching statistical significance, encouraging trends were observed in the MMAE group, including the absence of reoperations, lower recurrences, greater reductions in cSDH thickness, and a further reduction in midline shift despite earlier initiation of antithrombotic medications.

While the indications for MMAE are still largely undefined, its widespread use has led to several active clinical trials evaluating its efficacy. Concurrent with the aging population, patients often require early resumption of antithrombotics (ACs or APs) in the immediate postoperative period following surgical evacuation. The addition of MMAE after surgical evacuation thus appears appealing in the subgroup of patients who need early antithrombotic therapy. Our results indicate that there is no clear benefit of MMAE in reducing the risk of recurrence (symptomatic or radiological) in patients started on antithrombotics.

Interestingly, both recurrence and reoperation appeared to be lower in the MMAE group, but these differences were not statistically significant. Similarly, patients in the MMAE + surgery group were restarted on antithrombotics significantly earlier than those in the surgery-alone group. This suggests that the treating neurosurgeons were more aggressive after MMAE compared to surgery alone, which may be a factor contributing to an increased risk of recurrence. Finally, secondary outcomes in the study also showed a favorable trend with the addition of MMAE, although changes in SDH thickness and midline shift did not reach statistical significance; both were better in the MMAE + surgery group.

It is well known that antithrombotics, especially ACs, are significant risk factors for cSDH formation and recurrences.^10,11) Furthermore, our prior report on this topic showed that rapid initiation of antithrombotics after MMAE for cSDH leads to higher rates of recurrence, with similar reoperation rates.¹²⁾ This finding indicates that antithrombotics, even in the setting of MMAE, continue to pose a risk for recurrence. Herein, we show that adding MMAE to surgical evacuation does not confer a clear benefit against recurrence or reoperation rates with early initiation of antithrombotics (AT), despite some encouraging findings.

Limitations

The results are limited by the inherent limitations of a retrospective study design. Also, given the very specific nature of the question, the sample size remains relatively small. Furthermore, the earlier time of initiation of antithrombotics may have introduced bias against the MMAE + surgery group. There is no standardized treatment algorithm at our institution, and treatment decisions, including the indication for reoperation (the primary outcome), were left to the discretion of the treating neurosurgeon. As MMAE has become more frequently used, the tolerance for early residual/recurrent cSDH may have changed. Finally, the use of different study periods for the 2 comparison groups may introduce selection bias.

Conclusion

We report the largest series focusing on MMAE as an adjunct to surgery for cSDH in the setting of early initiation of antithrombotics. While our sample size is small, there is no clear benefit of adding MMAE to this subgroup of patients. Caution should be exercised when initiating early antithrombotics, even after MMAE. Further studies are needed to determine whether MMAE confers additional protection in this cohort.

Disclosure Statement

The authors declare that they have no conflicts of interest.

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