RESEARCH—HUMAN—CLINICAL STUDIES

James E. Siegler, MD
‡
* Endovascular Therapy for Cerebral Vein Thrombosis:
Liqi Shu, MD
Shadi Yaghi, MD ‡ A Propensity-Matched Analysis of Anticoagulation in
Setareh Salehi Omran, MD §
the Treatment of Cerebral Venous Thrombosis
||
Marwa Elnazeir, MD
¶
Ekaterina Bakradze, MD BACKGROUND: Endovascular treatment (EVT) for cerebral vein thrombosis (CVT) has not been
# proven to be more effective than anticoagulation based on recent results of the Thrombolysis or
Marios Psychogios, MD
Gian Marco De Marchis, MD, Anticoagulation for Cerebral Venous Thrombosis (TO-ACT) randomized clinical trial.
OBJECTIVE: To compare outcomes of EVT vs medical management in CVT.
MSc **
METHODS: We compared EVT vs medical management in a retrospective multinational
Siyuan Yu, BS*
cohort of consecutive patients with CVT across 4 countries (USA, Italy, Switzerland, and
Piers Klein†† New Zealand) and 27 sites (2015-2020), using propensity score matching (PSM) and
Mohamad Abdalkader, inverse probability treatment weighting (IPTW), and meta-analyzed these results with the
†† TO-ACT trial. The primary outcome was excellent functional outcome (modified Rankin
MD
Thanh N. Nguyen, MD †† Scale [mRS] 0-1) at 90 days.
RESULTS: Of the 987 patients, the mean age was 45.7 ± 16.9 years and 79 (8%) underwent
on behalf of the ACTION-CVT
EVT. With PSM (n = 124), there were no major differences in clinical or imaging features
Investigators
between groups other than a higher proportion of female patients receiving EVT (81% vs
*Department of Neurology, Cooper Neuro- 65%, P = .04). There was no difference in the primary outcome with PSM (odds ratio [OR]
logical Institute, Cooper University Hospital, 1.48, 95% CI, 0.55-3.96) or IPTW (OR 1.02, 95% CI, 0.34-3.06). EVT was associated with a higher
Camden, New Jersey, USA; ‡Department of 90-day shift in modified Rankin Scale (OR 2.00, 95% CI, 1.01-3.98) and mortality with IPTW
Neurology, Rhode Island Hospital, Brown
University, Providence, Rhode Island, USA; (OR 4.60, 95% CI, 1.10-19.23) but no other differences in secondary outcomes with PSM or
§
Department of Neurology, University of IPTW. A meta-analysis of primary and secondary outcomes from TO-ACT and PSM patients
Colorado School of Medicine, Aurora, Col- from anticoagulation in the treatment of cerebral venous thrombosis also showed no
orado, USA; ||Department of Neurology,
University of Massachusetts Medical School, significant association with EVT in primary or secondary outcomes.
Worcester, Massachusetts, USA; ¶Depart- CONCLUSION: In this large observational cohort, there was no evidence of benefit with
ment of Neurology, University of Alabama at EVT for CVT. These findings corroborate the results from the TO-ACT trial.
Birmingham, Birmingham, Alabama, USA;
#
Department of Neuroradiology & Stroke KEY WORDS: Cerebral vein thrombosis, Thrombectomy, Venous sinus thrombosis, Anticoagulation, Cerebral
Center, University Hospital Basel and Uni- edema, Inverse probability treatment weighting, Endovascular therapy
versity of Basel, Basel, Switzerland; **De-
partment of Neurology & Stroke Center, Neurosurgery 00:1–7, 2022 https://doi.org/10.1227/neu.0000000000002098
University Hospital Basel and University of
Basel, Basel, Switzerland; ††Department of
Neurology, Boston Medical Center, Boston,

C
Massachusetts, USA
erebral vein thrombosis (CVT) is an un- occluded cerebral vein or dural sinus with anti-
common but severe neurological emer- coagulation for 3 to 6 months.2,3 Endovascular
gency that can lead to rapid progression of treatment (EVT) in the form of thrombectomy
venous infarction and intracranial hypertension.1 is considered4,5 in patients for whom anti-
Correspondence: Definitive treatment entails recanalization of the coagulation may be contraindicated, or symp-
James E. Siegler, MD,
Cooper Neurological Institute, toms progress despite anticoagulation, and is
Cooper University Hospital, recommended with a low level of evidence by the
3 Cooper Plaza, Suite 320, ABBREVIATIONS: ACTION-CVT, anticoagulation in American Heart Association (Class IIb, Level of
Camden, NJ 08103, USA. the treatment of cerebral venous thrombosis; CVT,
Email: siegler.james@gmail.com cerebral vein thrombosis; EVT, endovascular
Evidence C).2 Systematic review and meta-
Twitter: @JimSiegler
treatment; ICH, intracranial hemorrhage; IPTW, in- analyses indicate that EVT is reasonable and
verse probability treatment weighting; NIHSS, Na- safe as a salvage treatment for CVT, with similar
Received, February 23, 2022.
Accepted, June 5, 2022.
tional Institutes of Health Stroke Scale; PSM, patient outcomes compared with medically
Published Online, August 23, 2022. propensity score matching; TO-ACT, Thrombolysis managed patients.6,7 However, these data are
or Anticoagulation for Cerebral Venous Thrombosis.
limited by small patient populations, with the
© Congress of Neurological Surgeons
2022. All rights reserved.
Supplemental digital content is available for this article at largest cohort comprising 63 patients.8 Fur-
neurosurgeryonline.com.
thermore, the adjunctive benefit of endovascular

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SIEGLER ET AL
treatment in CVT was not proven in the TO-ACT multicenter
randomized clinical trial.9 In Thrombolysis or Anticoagulation
for Cerebral Venous Thrombosis (TO-ACT), the likelihood of
achieving a good functional outcome (modified Rankin Scale
[mRS] 0-1) was no different between the endovascular and
medically managed arms.
We sought to characterize the safety and efficacy of EVT in a
large, multinational observational cohort of patients with acute
CVT outside of the clinical trial realm.
METHODS
Deidentified data will be made available on reasonable request of the
corresponding author.
Patient Population
Patient demographics and clinical characteristics from the anticoagulation
in the treatment of cerebral venous thrombosis (ACTION-CVT) multi-
center cohort have been previously described.10 ACTION-CVT included
1025 consecutive patients with CVT treated between January 2015 and
December 2020 at 27 sites in 4 countries. In the present analysis, patients
from ACTION-CVT were categorized into medical management and
EVT arms. Patients were excluded if they had a concomitant dural arte-
riovenous fistula (which might have required endovascular intervention
separately from the vein thrombosis). Medical management included the
use of unfractionated or low molecular weight heparin, vitamin K an-
tagonists, direct oral anticoagulants, or a combination of the above. A
subgroup of patients from ACTION-CVT underwent EVT at the dis-
cretion of local clinicians. EVT included mechanical clot retrieval with or
without local thrombolysis.
Statistical Methods
Continuous variables are summarized using means with standard
deviation when normally distributed and are compared using unpaired
t tests, whereas continuous variables that are non-normally distributed are
summarized using medians with interquartile range and compared using
the Wilcoxon rank-sum test. The χ 2 test was used to compare differences
between categorical variables, which are summarized as proportions.
The primary outcome was excellent functional outcome (mRS 0-1)9,11 at
90 days after CVT. Secondary outcomes included successful recanalization
and ordinal shift in the mRS at 90 days. Successful recanalization was
adjudicated by local site investigators as recanalization within 180 days
(among patients who underwent repeat vascular imaging) and was cate-
gorized as “complete,” “partial,” or “none.” Safety outcomes were considered
if they occurred after EVT or initiation of medical management and in-
cluded worsening vasogenic edema and/or new venous infarction, symp-
tomatic intracranial hemorrhage (defined by any new/worsening intracranial
hemorrhage [ICH] causing new/worsening symptoms), and death by 90
days. Propensity score matching (PSM) without replacement was used to
generate subpopulations based on treatment with EVT to reduce con-
founding by treatment indication, with estimates calculated based on the
propensity score of receiving EVT according to age, clinical symptoms of
encephalopathy or coma, National Institutes of Health Stroke Scale
(NIHSS), deep vein thrombosis (internal cerebral veins, straight sinus, or
vein of Galen), edema and/or ICH on neuroimaging (using head computed
tomography or MRI), and neurosurgical intervention. Separately, we
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modeled each outcome using inverse probability treatment weighting
(IPTW),12 with adjustment for each of the abovementioned covariates.
Standardized differences between the 2 subpopulations were calculated, with
a difference of ±0.20 indicating significant imbalance (Table 1).13 Logistic
regression was used to estimate the effect of EVT vs medical management on
the primary and secondary outcomes of interest, with effect estimates shown
as odds ratios (ORs) with 95% CIs. Unadjusted logistic regression models
with clustering were generated using the PSM cohort to study associations
between EVT and primary and secondary outcomes.
A sensitivity analysis was performed restricting inclusion to patients who
would have met inclusion criteria for the TO-ACT trial (Supplemental
Digital Content, http://links.lww.com/NEU/D254, http://links.lww.
com/NEU/D255, http://links.lww.com/NEU/D256),9 with further ad-
justment using PSM and IPTW as above. Data from the ACTION-CVT
PSM sensitivity cohort and TO-ACT were meta-analyzed with risk ratios
using a restricted maximum likelihood random effects model. The fol-
lowing outcomes between the 2 studies shared similar definitions; therefore,
risk ratios with 95% CIs were calculated for these events: mRS 0 to 1 and
mRS 0 to 2 (assessed at 6 months from TO-ACT and 3 months from
ACTION-CVT), symptomatic intracranial hemorrhage (defined as neu-
rological worsening due to new or progressive ICH in ACTION-CVT or a
worsening in NIHSS of ≥4 points due to ICH in TO-ACT), and death (at
3 months from ACTION-CVT and 6 months from TO-ACT).
Stata/SE 15.1 was used for all statistical analyses. All tests were per-
formed at the 2-sided level, with an alpha set at 0.05. No adjustments
were made for multiple hypothesis testing. As this was a post hoc analysis
of an existing cohort, no sample size calculations were made. Missing data
were not imputed, and patients without mRS scores at the follow-up were
excluded from analyses of mRS assessment. These results are described in
accordance with Strengthening the Reporting of Observational Studies in
Epidemiology guidelines. This study was approved by the local regulatory
board of each participating center with waiver of informed consent
because it involved the retrospective collection of existing data.
RESULTS
Of the 1025 patients from the original ACTION-CVT cohort,
987 (96%) had complete demographic and treatment data for this
analysis and were included. The mean age of included patients was
45.7 years (±16.9), 630 (63%) were female, and the median NIHSS
was 0 (IQR 0-3). Patients were well-matched except for EVT-treated
patients presenting more frequently with focal neurological deficits,
encephalopathy, and had more severe NIHSS (P < .05; Table 1).
The initial imaging was more likely to show venous infarction,
cerebral edema, and parenchymal hemorrhage, and the occlusive
lesion was more likely to involve both the superficial and deep veins
among EVT-treated patients (P < .05; Table 1). Only 1 patient in
the EVT group did not receive therapeutic anticoagulation.
In the IPTW model, EVT was not associated with higher odds
of excellent functional outcome when compared with medical
management (IPTW adjusted OR 1.02, 95% CI, 0.34-3.06; Ta-
ble 2). When stratified by final recanalization rate, the odds of ex-
cellent functional outcome were not significantly different among
EVT patients with successful recanalization when compared
with EVT patients with partial/no recanalization (N = 29, 10/11
[90.9%] vs 15/18 [83.3%], IPTW adjusted OR 10.10, 95% CI,
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 ENDOVASCULAR THERAPY FOR CEREBRAL VEIN THROMBOSIS

TABLE 1. Unweighted and Weighted Patient Demographics and Clinical Characteristics

Unweighted Propensity score matched

Medical Endovascular Unweighted Medical Endovascular Weighted

management treatment P standardized management treatment P standardized
(n = 908) (n = 79) value difference (n = 62) (n = 62) value difference

Age, mean (SD) 45.89 ± 17.13 42.83 ± 14.25 .124 0.194 41.31 ± 13.08 41.58 ± 13.7 .911 0.020
Female, no. (%) 568/908 (62.6%) 60/79 (75.9%) .018 0.292 40/62 (64.5%) 50/62 (80.6%) .044 0.365
Race, no. (%)
White 642/902 (71.2%) 47/78 (60.3%) .043 0.231 35/59 (59.3%) 36/61 (59.0%) .973 0.006
Black 137/902 (15.2%) 19/78 (24.4%) .034 0.231 16/59 (27.1%) 15/61 (24.6%) .752 0.057
Asian/other 123/908 (13.5%) 12/79 (15.2%) .683 0.047 8/62 (12.9%) 10/62 (16.1%) .610 0.091
Hispanic, no. (%) 87/897 (9.7%) 6/79 (7.6%) .541 0.075 5/60 (8.3%) 6/62 (9.7%) 1.000 0.047
Time from symptom to 4 (1-10) 3 (1-7) .117 0.090 3 (1-10) 3 (1-8) .998 0.023
admission, median days
(IQR)
Time from symptom to 5 (2-12) 3 (2-7) .017 0.117 4 (2-15) 3 (2-8) .743 0.001
treatment, median days
(IQR)
Medical history, no. (%)
Contraceptive use 209/890 (23.5%) 25/79 (31.6%) .104 0.183 20/62 (32.3%) 22/62 (35.5%) .704 0.068
Tobacco use 122/902 (13.5%) 14/79 (17.7%) .301 0.115 7/61 (11.5%) 12/62 (19.4%) .227 0.218
Active cancer 59/906 (6.5%) 2/79 (2.5%) .222 0.192 2/61 (3.3%) 2/62 (3.2%) 1.000 0.003
Antiphospholipid 11/884 (1.2%) 0/79 (0.0%) 1.000 0.159 0/62 (0.0%) 0/62 (0.0%)
antibody syndrome
COVID-19, among tested 6/131 (4.6%) 2/9 (22.2%) .084 0.511 1/13 (7.7%) 2/9 (22.2%) .544 0.394
Clinical symptoms, no. (%)
Headache 678/907 (74.8%) 63/78 (80.8%) .237 0.145 45/62 (72.6%) 52/62 (83.9%) .128 0.274
Focal deficit 347/908 (38.2%) 41/78 (52.6%) .013 0.290 29/62 (46.8%) 31/62 (50.0%) .719 0.064
Seizure 218/908 (24.0%) 18/78 (23.1%) .853 0.022 27/62 (43.5%) 15/62 (24.2%) .023 0.414
Encephalopathy 166/908 (18.3%) 34/78 (43.6%) .000 0.567 30/62 (48.4%) 27/62 (43.5%) .589 0.096
Coma 22/908 (2.4%) 4/78 (5.1%) .143 0.142 5/62 (8.1%) 3/62 (4.8%) .717 0.131
Baseline NIHSS, median 0 (0-2) 3 (0-12) .000 0.648 2 (0-8) 2 (0-11) .565 0.032
(IQR)
Imaging findingsa, no. (%)
Venous infarction 226/908 (24.9%) 39/79 (49.4%) .000 0.522 23/62 (37.1%) 30/62 (48.4%) .204 0.228
Cerebral edema 263/908 (29.0%) 39/79 (49.4%) .000 0.426 32/62 (51.6%) 32/62 (51.6%) 1.000 0.000
Parenchymal hemorrhage 326/908 (35.9%) 46/79 (58.2%) .000 0.457 34/62 (54.8%) 33/62 (53.2%) .857 0.032
Superficial vein only 670/906 (74.0%) 42/79 (53.2%) .000 0.441 36/62 (58.1%) 33/62 (53.2%) .588 0.097
Deep vein onlyb 99/906 (10.9%) 13/79 (16.5%) .138 0.161 14/62 (22.6%) 9/62 (14.5%) .248 0.207
Cortical vein (s) only 27/906 (3.0%) 1/79 (1.3%) .720 0.119 0/62 (0.0%) 1/62 (1.6%) 1.000 0.180
Deep and superficial vein 106/906 (11.7%) 23/79 (29.1%) .000 0.441 12/62 (19.4%) 19/62 (30.6%) .147 0.261
Therapeutic 908/908 78/79 (98.7%) .080 0.159 62/62 (100.0%) 62/62 (100.0%)
anticoagulation, no. (%) (100.0%)
Neurosurgical treatment 35/908 (3.9%) 20/79 (25.3%) .000 0.635 13/62 (21.0%) 14/62 (22.6%) .828 0.039

COVID-19, coronavirus disease 2019; NIHSS, National Institutes of Health Stroke Scale.
a
Imaging findings were reported as present if they were identified on computed tomography, magnetic resonance imaging, or both.
b
Deep vein involvement was defined as a thrombus within the internal cerebral veins, straight sinus, or vein of Galen.

0.53-194.23). When compared with all patients who underwent
medical management, patients with EVT and complete recanaliza-
tion had significantly greater odds of achieving an excellent functional
(N = 524, 10/11 [90.9%] vs 410/513 [79.9%], IPTW adjusted OR
11.88, 95% CI, 2.88-49.04). Among patients with superficial vein
involvement, the odds of excellent functional outcome were similar
with EVT vs medical management (N = 539, 15/25 [60.0%] vs 411/
514 [80.0%], IPTW adjusted OR 0.76 95% CI, 0.22-2.69).
In the PSM cohort of 124 patients, EVT was not associated
with higher odds of the primary outcome (OR 1.48, 95% CI,
0.46-4.75) or any secondary outcomes (P > .05; Table 2). With
IPTW, including adjustment for covariates in the PSM model, in
addition to neurosurgical treatment, there were no significant
differences in the primary outcome (OR 1.02, 95% CI, 0.34-
3.06). However, EVT was associated with higher mRS shift (OR
2.00, 95% CI, 1.01-3.98; Figure 1) and mortality at 90 days (OR

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SIEGLER ET AL

TABLE 2. Primary and Secondary Outcomes

Medical Endovascular Crude odds IPTW odds PSM odds

management treatment ratio P ratioa (95% CI) P ratiob (95% CI) P
(n = 908) (n = 79) (95%CI) value (n = 819) value (n = 124) value

Primary outcome
Excellent functional outcome 445/566 (78.6%) 36/56 (64.3%) 0.489 .066 1.018 .974 1.476 .439
(mRS 0-1 at 90 days), no. (%) (0.228-1.049) (0.339-3.055) (0.551-3.955)
Secondary outcomes
Good functional outcome 493/566 (87.1%) 37/56 (66.1%) 0.288 .001 0.48 (0.164- .179 0.895 .822
(mRS 0-2 at 90 days), no. (%) (0.135-0.614) 1.401) (0.341-2.353)
mRS at 90 daysc, median (IQR) 0 (0-1) 1 (0-4) 2.451 .005 1.999 .048 0.851 .696
(1.307-4.600) (1.005-3.977) (0.379-1.911)
Complete recanalization 156/513 (30.4%) 12/46 (26.1%) 0.808 .483 0.701 .246 0.578 .227
by 180 days, no. (%) (0.444-1.468) (0.385-1.278) (0.237-1.406)
Complete recanalization, 255/675 (37.8%) 23/57 (40.4%) 1.114 .534 0.737 .243 0.690 .191
no. (%) (0.792-1.567) (0.441-1.23) (0.395-1.203)
Imaging outcomes
New or worsening vasogenic 57/908 (6.3%) 7/79 (8.9%) 1.452 .338 0.55 (0.135-2.24) .404 0.407 .124
edema or progressive venous (0.678-3.109) (0.129-1.281)
infarction, no. (%)
Symptomatic intracranial 19/908 (2.1%) 2/79 (2.5%) 1.215 .725 1.243 .731 2.033 .545
hemorrhage, no. (%) (0.409-3.609) (0.36-4.292) (0.205-20.215)
Death by 90 days, no. (%) 34/908 (3.7%) 6/79 (7.6%) 2.113 .110 4.601 .036 0.786 .730
(0.845-5.282) (1.101-19.227) (0.200-3.089)

EVT, endovascular treatment; IPTW, inverse probability treatment weighting; mRS, modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale; PSM, propensity score matching.
a
IPTW was adjusted for age, NIHSS, clinical symptoms of encephalopathy/coma, the presence of cerebral edema and/or parenchymal hemorrhage on baseline imaging, deep vein
involvement, and neurosurgical treatment.
b
Estimates of PSM were calculated based on the propensity score of receiving EVT using logistic regression according to age, clinical symptoms of encephalopathy or coma, NIHSS,
thrombosis of a deep intracerebral vein (internal cerebral veins, straight sinus, or vein of Galen), and the radiographic presence of edema and/or hemorrhage on neuroimaging
(using head computed tomography or MRI) and neurosurgical intervention.
c
Odds ratios calculated using proportional hazards model for shift indicating favorable treatment effect.

4.60, 95% CI, 1.10-19.23). There were no other differences in
outcomes with respect to treatment in the IPTW model.
TO-ACT Sensitivity Analysis
Among TO-ACT eligible patients (n = 583; Supplemental
Digital Content 1, http://links.lww.com/NEU/D254), there were
no major differences in demographics between treatment groups
other than the EVT patients having more severe NIHSS (median 5
[IQR 0-14] vs 1 [IQR 0-4], P < .001), more frequent encepha-
lopathy (49% vs 28%, P < .001), and less frequent seizure at onset
(21% vs 34%, P = .03; Supplemental Digital Content 2, http://
links.lww.com/NEU/D255). After PSM and IPTW, there was no
significant difference in the odds of achieving excellent functional
outcome with EVT vs medical management (IPTW OR 0.53, 95%
CI, 0.15-1.91; PSM OR 1.10, 95% CI, 0.31-3.91; Supplemental
Digital Content 3, http://links.lww.com/NEU/D256). In the PSM
analysis, there were no differences among the secondary outcomes
between the management groups, other than death by 90 days which
was significantly greater among the EVT patients (OR 12.12, 95%
CI, 1.66-88.68). The greater odds of death were also observed with
EVT in the IPTW analysis (OR 10.20, 95% CI, 2.08-49.98). The
odds of new or progressive edema/infarction were lower with EVT in
the IPTW model (OR 0.24, 95% CI, 0.06-0.96), although EVT
patients were at lower odds of a good functional outcome (90-day
mRS 0-2 OR 0.22, 95% CI, 0.07-0.72) and had a less favorable shift
in the mRS at 90 days (OR 2.83, 95% CI, 1.20-6.67).
After consolidating the ACTION-CVT PSM cohort with
the TO-ACT cohort in a meta-analysis, there were no statistically
significant differences in EVT vs medical management for the
primary outcome of excellent functional outcome (RR 1.10, 95%
CI, 0.82-1.47) and no significant difference across the secondary
outcomes (Figure 2).
DISCUSSION
Key Results
This analysis of the ACTION-CVT multicenter cohort study
represents the largest observational cohort study of patients with CVT
who underwent medical or EVT management to our knowledge.
Despite key differences in clinical symptoms, CVT location, and
radiographic findings between treatment groups, these differences were
pseudonormalized with PSM to estimate differences in outcomes
between treatment groups. We found no difference in excellent
functional outcome (mRS 0-1) at 90 days and no difference in
secondary clinical or radiographic outcomes with EVT over medical

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 ENDOVASCULAR THERAPY FOR CEREBRAL VEIN THROMBOSIS

FIGURE 1. Ninety-day mRS scores according to the treatment group from the PSM analyses. EVT, endovascular
treatment; MM, medical management; mRS, modified Rankin Scale; PSM, propensity score matching.

treatment of CVT. In a sensitivity analysis limiting inclusion of pa-
tients based on eligibility for the TO-ACT randomized clinical trial,
there was no significant difference in the prespecified primary outcome
based on treatment using PSM or IPTW modeling. However, there
was a signal toward worse functional outcomes among patients
managed using EVT with a higher mortality rate by 90 days.
Our findings reflect the observations and management strat-
egies of 27 centers in 4 countries. It is possible that the lack of
benefit of EVT in the primary analysis may be attributed to a
ceiling effect. Given the high probability of achieving this fa-
vorable outcome irrespective of EVT, the chances of observing an
even greater improvement are expected to be attenuated. For this

FIGURE 2. Meta-analysis of anticoagulation in the treatment of cerebral venous thrombosis PSM and TO-ACT cohorts. Forest plots illustrating differences between EVT and
MM for the odds of A, primary outcome (mRS 0-1 at 90 days), B, mRS 0 to 2 at 90 days, C, symptomatic intracranial hemorrhage, and D, death by 180 days. EVT,
endovascular treatment; MM, medical management; mRS, modified Rankin Scale; PSM, propensity score matching.

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SIEGLER ET AL
reason, we explored other clinical and radiographic outcomes.
However, we found no consistent signal of benefit with EVT for
any of these radiographic or clinical end points in PSM or IPTW
modeling. Furthermore, the benefit of EVT may be appreciated in
other outcomes, such as relief of headache symptoms, improved
quality of life, shorter length of hospitalization, and reduced costs.
However, these data were not captured in ACTION-CVT.
In the largest multicenter observational cohort study to date
(n = 624), the International Study of Cerebral Vein and Dural
Sinus Thrombosis (ISCVT) investigators found that excellent
functional outcome (mRS 0-1) was achieved in 79% of patients by
16 months14; however, only 2% underwent EVT, precluding an
exploratory analysis of EVT-associated outcomes. An earlier,
multicenter cohort (n = 182) by Wasay et al15 found that 27% of
patients achieved an excellent outcome at 1 year (mRS 0-1).
Although the outcomes were poorer in the cohort described by
Wasay et al,15 when compared with ACTION-CVT, these pa-
tients more frequently presented with coma (20% vs 2%) and less
frequently received any anticoagulation (9% vs ∼0%). It is likely
that more sensitive neuroimaging, heightened awareness of CVT
for milder disease, improvement in endovascular techniques, and
earlier and aggressive medical management with anticoagulation
because these data were originally collected (1991-2001)15 and
may explain the improved outcomes seen in ISCVT and AC-
TION-CVT. The increase in utilization of endovascular treat-
ment, despite the fact that nearly 100% of patients with
ACTION-CVT were concomitantly anticoagulated, may be
explained by recent efficacy of EVT in acute stroke treatment and
advances in catheter technology.16,17
TO-ACT remains the only published randomized clinical trial
evaluating safety and efficacy of endovascular treatment of acute
CVT but did not demonstrate superiority of endovascular in-
tervention.9 The investigators are to be commended for running a
CVT trial for a relatively rare disease. It is possible that a treatment
effect may have been observed with a larger cohort or that EVT
may only benefit a certain subpopulation of patients with CVT. In
our sensitivity analysis, which closely mimicked the inclusion
criteria from TO-ACT, we found no significant differences in
outcomes based on treatment strategy.
Limitations
This study remains limited by its nonrandomized treatment
allocation and retrospective nature. Perhaps most importantly,
discrete data regarding indications or need for EVT were not
captured and likely led to residual confounding. For example,
NIHSS was only collected on admission. Patients may have
deteriorated after medical treatment and then went for EVT. This
is partially reflected by the higher rate of neurosurgical inter-
vention in the EVT arm. Severity of clinical and imaging findings
may also have been completely captured by the variables in our
registry. Although we matched patients based on the presence or
absence of hemorrhage, edema, and venous infarction, we do not
compare differences in severity (eg, volume and midline shift) or
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endovascular technique (eg, aspiration, stent-retriever, and local
thrombolysis). Finally, patients in this cohort were treated using
endovascular techniques as early as 2015, with potentially less
efficacious devices or approaches. At this time, several landmark
trials were published indicating efficacy with intracranial arterial
thrombectomy using some first-generation and second-generation
devices. Although we did not collect data regarding devices or
techniques on the patient level, the most commonly reported
practice among proceduralists at our centers involves aspiration
without local thrombolysis. That said, there has been only 1 well-
designed clinical trial evaluating endovascular treatment of an
intracranial venous occlusion, so it remains unknown if arterial and
venous thrombectomy techniques are even comparable. The lack
of standardized technique in the endovascular arm may also have
reduced the potential efficacy of this intervention. A more ho-
mogeneous treatment approach should be considered in future
clinical trials.
CONCLUSION
Interpretation
Altogether, our findings provide real-world data supporting the
TO-ACT trial results. It is possible that only a subgroup (or
subgroups) of patients with CVT may benefit from EVT (eg,
refractory intracranial hypertension, progressive venous infarc-
tion, or hemorrhage expansion), and this needs to be determined
by future randomized clinical trials. Furthermore, among the few
patients who underwent successful recanalization with EVT and
had available recanalization and long-term follow-up data (n =
11), there was a suggestion of improved outcomes when compared
with patients treated using medical management. This warrants
validation in a larger data set or randomized clinical trial.
Generalizability
Despite the limitations of this study design, this remains a large
observational cohort study of patients treated with EVT or
medical management for CVT across a diverse population. Al-
though we modeled clinical and radiographic outcomes using
PSM and IPTW to account for the nonrandomized treatment
allocation, we found no significant benefit of EVT in CVT in the
primary analysis. Poorer outcomes were observed among several
secondary end points and in sensitivity analyses, which may be
related to residual confounding or complications of EVT.
However, there was a suggestion of benefit with EVT when
successful recanalization was achieved.
Funding
This study did not receive any funding or financial support.
Disclosures
The authors have no personal, financial, or institutional interest in any of the
drugs, materials, or devices described in this article. Dr Siegler reports speakers
neurosurgery-online.com

bureau (AstraZeneca) and consulting fees (Ceribell), unrelated to the present work.
Dr Nguyen reports research support from Medtronic and the Society of Vascular
and Interventional Neurology, unrelated to present work. Dr De Marchis reports
travel support from Medtronic; travel support from Pfizer; and compensation from
Bayer for consultant services, all unrelated to the present work.
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Acknowledgments
The authors would like to acknowledge Ray Tanzer, PhD, from Lifespan
Biostatistics Core.
Supplemental digital content is available for this article at neurosurgeryonline.com.
Supplemental Digital Content 1. Major inclusion/exclusion criteria from
TO-ACT with approximated definitions derived from ACTION-CVT for the
sensitivity analysis.
Supplemental Digital Content 2. Demographics for sensitivity analysis (ap-
proximating inclusion criteria from the TO-ACT trial).
Supplemental Digital Content 3. Primary and secondary outcomes of the
sensitivity analysis (approximating inclusion criteria from the TO-ACT trial).
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