Quick search in Citations
This JournalAnywhereCitation
Advanced Search
Research Article
Originally Published 10 February 2022
Free Accessfeatured article

Direct Oral Anticoagulants Versus Warfarin in the Treatment of Cerebral Venous Thrombosis (ACTION-CVT): A Multicenter International Study

Shadi Yaghi, MD https://orcid.org/0000-0003-0031-1004 [email protected], Liqi Shu, MD https://orcid.org/0000-0002-9784-8475, Ekaterina Bakradze, MD https://orcid.org/0000-0001-7534-7218, Setareh Salehi Omran, MD https://orcid.org/0000-0002-3184-5327, James A. Giles, MD https://orcid.org/0000-0002-3197-3062, Jordan Y. Amar, MD, Nils Henninger, MD, PhD, Dr med https://orcid.org/0000-0002-3883-5623, … Show All … , Marwa Elnazeir, MD, Ava L. Liberman, MD https://orcid.org/0000-0003-0184-6035, Khadean Moncrieffe, BS https://orcid.org/0000-0002-2310-4609, Jenny Lu, BS https://orcid.org/0000-0002-4259-5677, Richa Sharma, MD https://orcid.org/0000-0003-0798-2353, Yee Cheng, MD, Adeel S. Zubair, MD, Alexis N. Simpkins, MD, PhD, MSCR https://orcid.org/0000-0001-7529-4267, Grace T. Li, MD https://orcid.org/0000-0001-9983-2672, Justin Chi Kung, BS https://orcid.org/0000-0002-1382-2711, Dezaray Perez, BS https://orcid.org/0000-0003-4060-3001, Mirjam Heldner, MD https://orcid.org/0000-0002-3594-2159, Adrian Scutelnic, MD https://orcid.org/0000-0001-9053-584X, David Seiffge, MD https://orcid.org/0000-0003-3890-3849, Bernhard Siepen, MD, Aaron Rothstein, MD https://orcid.org/0000-0002-8480-8220, Ossama Khazaal, MD https://orcid.org/0000-0002-8308-6596, David Do, MD https://orcid.org/0000-0003-3604-5609, Sami Al Kasab, MD https://orcid.org/0000-0001-8909-9761, Line Abdul Rahman, MD https://orcid.org/0000-0002-6660-032X, Eva A. Mistry, MD https://orcid.org/0000-0002-7426-3650, Deborah Kerrigan, MD https://orcid.org/0000-0002-1722-6677, Hayden Lafever, BS, Thanh N. Nguyen, MD https://orcid.org/0000-0002-2810-1685, Piers Klein https://orcid.org/0000-0001-7468-137X, Hugo Aparicio, MD https://orcid.org/0000-0001-8584-1455, Jennifer Frontera, MD https://orcid.org/0000-0002-0719-2522, Lindsey Kuohn, BS https://orcid.org/0000-0001-9500-6162, Shashank Agarwal, MD https://orcid.org/0000-0001-5097-416X, Christoph Stretz, MD https://orcid.org/0000-0003-4125-4077, Narendra Kala, MD, Sleiman El Jamal, MD https://orcid.org/0000-0002-4732-0170, Alison Chang, BS, Shawna Cutting, MD https://orcid.org/0000-0002-0072-7248, Han Xiao, MPH https://orcid.org/0000-0002-6770-7700, Adam de Havenon, MD https://orcid.org/0000-0001-8178-8597, Varsha Muddasani, MD https://orcid.org/0000-0002-4225-8558, Teddy Wu, MD https://orcid.org/0000-0003-1845-1769, Duncan Wilson, MD, Amre Nouh, MD, Syed Daniyal Asad, MD https://orcid.org/0000-0001-9377-8353, Abid Qureshi, MD https://orcid.org/0000-0002-1498-6638, Justin Moore, MD https://orcid.org/0000-0002-6002-0455, Pooja Khatri, MD https://orcid.org/0000-0002-7344-8266, Yasmin Aziz, MD https://orcid.org/0000-0002-3515-4005, Bryce Casteigne, MD https://orcid.org/0000-0002-3621-2158, Muhib Khan, MD https://orcid.org/0000-0001-6329-8703, Yao Cheng, MD, Brian Mac Grory, MD https://orcid.org/0000-0003-3914-8419, Martin Weiss, MD, Dylan Ryan, MD https://orcid.org/0000-0001-7254-0020, Maria Cristina Vedovati, MD, Maurizio Paciaroni, MD https://orcid.org/0000-0002-5483-8795, James E. Siegler, MD https://orcid.org/0000-0003-0287-3967, Scott Kamen, BS https://orcid.org/0000-0003-4473-9272, Siyuan Yu, BS https://orcid.org/0000-0001-7345-8088, Christopher R. Leon Guerrero, MD https://orcid.org/0000-0002-5997-5342, Eugenie Atallah, MD https://orcid.org/0000-0002-5594-9059, Gian Marco De Marchis, MD, MSc https://orcid.org/0000-0002-0342-9780, Alex Brehm, MD https://orcid.org/0000-0002-1630-6210, Tolga Dittrich, MD https://orcid.org/0000-0002-9987-3631, Marios Psychogios, MD https://orcid.org/0000-0002-0016-414X, Ronald Alvarado-Dyer, MD https://orcid.org/0000-0002-6902-2510, Tareq Kass-Hout, MD, Shyam Prabhakaran, MD https://orcid.org/0000-0003-0724-1694, Tristan Honda, BS https://orcid.org/0000-0001-9999-230X, David S. Liebeskind, MD https://orcid.org/0000-0002-5109-8736, and Karen Furie, MD https://orcid.org/0000-0003-0065-3784Author Info & Affiliations
Stroke
Volume 53, Number 3
https://doi.org/10.1161/STROKEAHA.121.037541
Track CitationsAdd to favorites
PDF/EPUB
VIEW EDITORIAL:ACTION-CVT: Are the Findings ACTIONable?

Abstract

Background:

A small randomized controlled trial suggested that dabigatran may be as effective as warfarin in the treatment of cerebral venous thrombosis (CVT). We aimed to compare direct oral anticoagulants (DOACs) to warfarin in a real-world CVT cohort.

Methods:

This multicenter international retrospective study (United States, Europe, New Zealand) included consecutive patients with CVT treated with oral anticoagulation from January 2015 to December 2020. We abstracted demographics and CVT risk factors, hypercoagulable labs, baseline imaging data, and clinical and radiological outcomes from medical records. We used adjusted inverse probability of treatment weighted Cox-regression models to compare recurrent cerebral or systemic venous thrombosis, death, and major hemorrhage in patients treated with warfarin versus DOACs. We performed adjusted inverse probability of treatment weighted logistic regression to compare recanalization rates on follow-up imaging across the 2 treatments groups.

Results:

Among 1025 CVT patients across 27 centers, 845 patients met our inclusion criteria. Mean age was 44.8 years, 64.7% were women; 33.0% received DOAC only, 51.8% received warfarin only, and 15.1% received both treatments at different times. During a median follow-up of 345 (interquartile range, 140–720) days, there were 5.68 recurrent venous thrombosis, 3.77 major hemorrhages, and 1.84 deaths per 100 patient-years. Among 525 patients who met recanalization analysis inclusion criteria, 36.6% had complete, 48.2% had partial, and 15.2% had no recanalization. When compared with warfarin, DOAC treatment was associated with similar risk of recurrent venous thrombosis (aHR, 0.94 [95% CI, 0.51–1.73]; P=0.84), death (aHR, 0.78 [95% CI, 0.22–2.76]; P=0.70), and rate of partial/complete recanalization (aOR, 0.92 [95% CI, 0.48–1.73]; P=0.79), but a lower risk of major hemorrhage (aHR, 0.35 [95% CI, 0.15–0.82]; P=0.02).

Conclusions:

In patients with CVT, treatment with DOACs was associated with similar clinical and radiographic outcomes and favorable safety profile when compared with warfarin treatment. Our findings need confirmation by large prospective or randomized studies.

Graphical Abstract

Cerebral venous thrombosis (CVT) is an uncommon cause of stroke, usually affecting younger patients.1 In the absence of contraindications, parenteral followed by oral anticoagulation is the recommended treatment.2 Randomized trials3–6 and guidelines7–9 indicate that direct oral anticoagulants (DOACs) are a viable and preferred alternative to warfarin for the treatment of patients with venous thromboembolism (VTE). Although the favorable safety and efficacy of DOACs in VTE treatment is frequently extrapolated to patients with CVT, limited data exist to support this approach.
See related article, p 739
The RESPECT-CVT trial (A Clinical Trial Comparing Efficacy and Safety of Dabigatran Etexilate With Warfarin in Patients With Cerebral Venous and Dural Sinus Thrombosis), which randomized 120 patients with CVT to dabigatran versus warfarin, showed no significant differences in efficacy and safety outcomes between the 2 treatment groups.10 However, this study was underpowered to show differences in safety or efficacy between the 2 groups due to the low rates of VTE recurrence and hemorrhagic complications.10 Therefore, it remains uncertain whether DOACs are as safe and effective as warfarin in patients with CVT. A better understanding of this issue is important since the pathomechanism(s) underlying CVT and VTE and their subsequent risks may differ.11,12
Large randomized controlled trials are challenging to conduct given the low incidence of CVT. Observational, real-world data may help answer whether treatment with DOACs versus warfarin is associated with similar efficacy and safety outcomes. In this study, we sought to compare the safety and efficacy of DOACs to warfarin in patients with CVT by collecting observational real-world data from large stroke centers worldwide.

Methods

Institutional Review Board approval was obtained from each participating center to perform the study. Informed Consent was waived by Institutional Board Review. De-identified data are available upon reasonable request to the corresponding author.

Patient Population

The ACTION-CVT (Anticoagulation in the Treatment of Cerebral Venous Thrombosis) study is a multicenter, international (United States, Italy, Switzerland, New Zealand; Figure S1) retrospective observational study that included consecutive adult patients with CVT confirmed on imaging admitted to each of the participating centers over a period of 6 years (January 1, 2015–December 31, 2020). Patients with CVT at each institution were initially identified using ICD-9 (325.0, 437.6, and 671.5) and ICD-10 codes (I67.6) with acceptable sensitivity and specificity.13,14 This was followed by review of medical records and imaging studies to confirm the diagnosis of CVT.
We excluded patients who were not treated with oral anticoagulation as well as patients in whom a specific anticoagulation strategy (DOAC or warfarin) would typically be used or preferred such as in the setting of antiphospholipid antibody syndrome associated CVT (warfarin is the drug of choice),15 active cancer (DOACs may be preferred over warfarin),16 and pregnancy (oral anticoagulation particularly with warfarin is contraindicated).17 For the recanalization analysis, we excluded patients who underwent endovascular treatment and those who were on both treatments (DOACs and warfarin) prior to completion of follow-up imaging.

Study Variables

The following variables were collected through medical record review:
Demographic factors: Age, sex, race (White, Black, or other), and ethnicity (Hispanic versus non-Hispanic).
CVT risk factors: Body mass index closest to the time of diagnosis, history of prior VTE, head trauma, lumbar puncture, mastoiditis/sinusitis within 3 months of CVT diagnosis, smoking history, oral contraceptive use, delivery within 12 weeks of CVT diagnosis, and family history of venous thrombosis.
Clinical variables: Days from first symptoms to diagnosis, duration of oral anticoagulation, days from initiation of anticoagulation to follow-up imaging, and clinical symptoms at presentation (headache, focal deficit, seizure, coma, etc.).
Imaging variables: Brain imaging findings (venous infarct, cerebral edema, or brain hemorrhage) and CVT location (deep venous sinus involvement versus no deep venous sinus involvement).
Laboratory variables closest to time of diagnosis: Platelet count, one or more antiphospholipid antibodies present at the time of diagnosis but not meeting criteria for antiphospholipid antibody syndrome at the time of evaluation, factor V Leiden mutation, and prothrombin gene mutation.
In-hospital treatments: Parenteral anticoagulation (low molecular weight heparin or intravenous heparin), endovascular treatment, and neurosurgical treatment (extra-ventricular drain or craniotomy).

Oral Anticoagulant Type

The primary predictor in this study was oral anticoagulant type (DOAC versus warfarin). Medical records were reviewed for compliance with anticoagulant therapy and international normalized ratio checks for patients prescribed warfarin. The times of oral anticoagulation initiation and cessation were recorded. In patients who remained on anticoagulation at the time of data abstraction, the last day of anticoagulation was considered as the last day of follow-up.

Outcomes

Study outcomes were abstracted by individual sites through review of all available medical records including outside hospital records at the time of data abstraction. The outcomes were (1) primary outcome: Recurrent venous thrombosis (VTE or CVT) during follow-up. Recurrent CVT included de novo CVT as well as extension of previous CVT occurring while on oral anticoagulation therapy. The inclusion of CVT extension is in line with the recurrent VTE definition in clinical trials4,5 and is an important outcome to capture in CVT patients as CVT progression can lead to worsening venous infarction, cerebral edema, hemorrhage, or increased intracranial pressure.
(2) Imaging outcomes: Recanalization status on last venous imaging study abstracted from radiology reports (no recanalization, partial recanalization, or complete recanalization). Complete recanalization was defined as full recanalization of the thrombosed vein or sinus without any residual thrombus. Partial recanalization was defined as improved opacification or flow in the affected cerebral sinus or vein, but with residual thrombus present on follow-up imaging. No recanalization was defined as no change or worsening in opacification or flow in the affected cerebral sinus or vein from baseline imaging.
(3) Safety outcomes: Major hemorrhage defined as new or worsening intracranial hemorrhage or major extracranial hemorrhage defined as systemic hemorrhage with at least 2 g/dL drop in hemoglobin level or requiring blood transfusion occurring while on oral anticoagulation therapy. Symptomatic intracranial hemorrhage was defined as any new or worsening intracranial hemorrhage on a follow-up brain imaging study causing new or worsening neurological signs or symptoms.
(4) Any death during follow-up.
All clinical outcomes were included if they occurred while on oral anticoagulation. Radiographic outcomes were included if the follow-up imaging study was done after initiation of oral anticoagulation.

Analytical Plan

Data verification was conducted by Drs Yaghi and Shu to ensure data integrity and consistency. Several queries were sent to participating sites regarding predictors, outcomes, and other variables. Missing data was not imputed. We used t test, χ2 test, Fisher exact test, or Wilcoxon rank-sum test (Mann-Whitney 2-sample statistic) as appropriate to compare co-variates between those with versus those without 90-day follow-up.
For univariate analyses, patients were divided into 2 groups based on the oral anticoagulant used: strictly warfarin versus strictly DOAC use. Analysis of clinical outcomes used the full data set, and end points occurring on oral anticoagulation counted against the drug in use at the time. Radiographic outcomes were only considered in patients using strictly one anticoagulant (DOAC or warfarin) prior to the follow-up venous imaging study. Between-group comparisons were done by t test, χ2 test, Fisher exact test or Wilcoxon rank-sum test (Mann-Whitney 2-sample statistic) as appropriate.
Unweighted and inverse probability of treatment weighted (IPTW) unadjusted and adjusted Cox-regression analyses with cluster frailty were used to test associations between oral anticoagulant type (DOAC versus warfarin) and clinical efficacy and safety outcomes. Patients who switched oral anticoagulant types were considered as crossovers from one arm to the other and analyzed using an as-treated approach. For each arm, the start of follow-up was considered as the time the oral anticoagulant was initiated and subjects were censored if they died, were lost to follow-up, or discontinued the oral anticoagulant prior to the outcome of interest. For the radiological outcome, we used unadjusted and adjusted binary logistic regression analyses to test associations between anticoagulant type and recanalization status. For the recurrent venous thrombosis outcome, we adjusted for variables associated with recurrent venous thrombosis in prior studies including age, sex, history of VTE,18,19 as well as the presence of one or more positive antiphospholipid antibodies that may portend an increased risk based on pathophysiological considerations. For the major hemorrhage and death outcome, we adjusted for predictors of intracranial and extracranial hemorrhage, age, sex, intracranial hemorrhage at baseline20,21 as well as deep CVT location, which is a predictor of poor functional outcome and mortality in CVT. The recanalization status outcome was adjusted for age, sex, intracranial hemorrhage at baseline, duration of anticoagulation therapy prior to follow-up imaging, and deep CVT location. These variables have either been shown to be directly or indirectly associated with recanalization status in prior studies,22 or are surrogate markers of thrombus burden and thus theoretically would be associated with lower likelihood of recanalization. Additional analyses were performed adding variables that differed between the 2 treatment groups (strictly DOACs versus strictly warfarin) to the models. Fully adjusted models included the prespecified variables above as well as variables that significantly differed between the 2 groups on univariate analysis, and these were used for IPTW weighting and propensity score matching.
Sensitivity analyses included propensity score matching (with and without replacement, caliper 0.05) to test the associations between anticoagulant type and study outcomes given differences between treatment groups at baseline. For the major hemorrhage outcome, a sensitivity analysis was performed excluding asymptomatic intracranial hemorrhages from the major hemorrhage outcome. Furthermore, as the recurrent CVT outcome included both CVT extension and de novo CVT, we attempted to investigate the effect of DOACs versus warfarin on each of the 2. Since our study could not differentiate between these 2 outcomes and since in the clinical setting, extension of a previous CVT is likely to occur in the early timeframe after diagnosis, we used time of recurrent CVT as a surrogate marker to identify CVT extension cases. We used Cox regression analyses to compare the effect on DOAC versus warfarin on recurrent CVT occurring at 0 to 90 days and >90 days from diagnosis, which represents the typical time frame for recanalization assessment. We also performed the same analyses using the 2-week time cutoff23 as well as the 4-week time cutoff. Additional sensitivity analyses were done for the IPTW models, excluding biologically plausible co-variates that lack supportive data to include described above. For major hemorrhage and recanalization, we excluded the co-variates baseline hemorrhage and deep venous involvement from the models; for recurrent VTE, we excluded the co-variate positive antiphospholipid antibodies from the models. We also ran separate IPTW models excluding patients with COVID-19 and those without 90-day follow-up.
For Cox regression models, proportionality was assessed using Schoenfeld residuals and parametric survival model was used when proportionality was not met. One year Kaplan-Meier survival curves of recurrent venous thrombosis, major hemorrhage, and death were plotted using unadjusted models with start of follow-up at the time of oral anticoagulation initiation and censoring at either an event of interest, death, loss of follow-up, or discontinuation/switch of oral anticoagulant therapy. Data were analyzed using Stata (version 15.1), and a P<0.05 was considered statistically significant.

Results

Among 1025 patients with CVT from 27 sites in the United States, Europe, and New Zealand (Figure S1), 845 patients met the inclusion criteria (Figure 1 depicts the study flow chart). The mean age of included subjects was 44.8 years, 64.7% (547) were women, and 84.3% (712) had at least 90-day follow-up; 33.0% (279) received DOAC only, 51.8% (438) received warfarin only, and 15.1% (128) received both treatments at different times. Among patients who used DOACs, 13.5% (55) used dabigatran, 18.2% (74) used rivaroxaban, and 66.6% (271) used apixaban, 1.7% (7) used other or multiple DOACs. The median (interquartile range) time from diagnosis to first follow-up imaging study was 102 (49–180) days.
Figure 1. Study flow chart (note that some patients may have more than one reason for exclusion). CVT indicates cerebral venous thrombosis; and DOAC, direct oral anticoagulants.
During a median follow-up of 345 (interquartile range, 140–720) days, there were 5.68 recurrent venous thromboses (17 VTE, 27 recurrent CVT, 2 had both VTE, and recurrent CVT), 3.77 major hemorrhages (23 intracranial hemorrhage [19 symptomatic and 4 asymptomatic] and 9 extracranial hemorrhages), and 1.84 deaths per 100 patient-years. Among 525 patients who met inclusion criteria for the recanalization outcome analysis, 192 (36.6%) had complete, 253 (48.2%) had partial, and 80 (15.2%) had no recanalization.
At least 90 day follow-up was available on 84.3% (712/845) of patients. compared with patients with <90 days of follow-up, patients with at least 90 days of follow-up data (n=712) were diagnosed later (4 days [interquartile range, 1–10] versus 3 days [interquartile range, 1–7]; P=0.033), had a higher BMI (29.6±7.7 versus 27.9±6.7; P=0.017), lower rates of tobacco use (11.7% versus 21.1%; P=0.004), and higher rate of endovascular treatment (9.7% versus 3.0%; P=0.011). Other characteristics were not significantly different between the 2 groups and are summarized in Table S1.

Univariate Analyses

In univariate analyses, when compared to patients treated strictly with warfarin, those treated strictly with DOACs were more likely to have a history of VTE (15.4% versus 6.6%, P<0.001), less likely to have one or more positive antiphospholipid antibodies (6.8% versus 12.1%, P=0.034), and less likely to have previously received low molecular weight heparin (33.3% versus 77.9%, P<0.001). Other characteristics including duration of anticoagulation and follow-up were not significantly different between the 2 groups (Table 1).
Table 1. Differences in Baseline Characteristics and Follow-Up Duration Across Patients Treated With DOAC Versus Warfarin
 Missing (n)DOAC only (n=279)Warfarin only (n=438)P value
Age (mean±SD)046.1±17.444.3±16.10.146
Sex (% women)0188/279(67.4%)276/438(63.0%)0.233
Race
 White7189/274(69.0%)326/436(74.8%)0.092
 Black747/274(17.2%)54/436(12.4%)0.077
 Asian715/274(5.5%)16/436(3.7%)0.252
Ethnicity (% Hispanic)725/274(9.1%)42/436(9.6%)0.821
Body mass index (mean±SD)4129.4±7.929.2±7.50.742
History of VTE043/279(15.4%)29/438(6.6%)<0.001
Family history of VTE331/276(11.2%)43/438(9.8%)0.546
Recent head trauma119/279(6.8%)35/437(8.0%)0.553
Recent mastoiditis or sinusitis029/279(10.4%)37/438(8.4%)0.379
Recent lumbar puncture011/279(3.9%)18/438(4.1%)0.912
Being within 12 weeks postpartum69/278(3.2%)17/433(3.9%)0.633
Oral contraceptive use1565/278(23.4%)117/424(27.6%)0.213
Active smoking328/277(10.1%)64/437(14.6%)0.078
Days from symptoms to diagnosis (median IQR)544 (1–10)4 (1–9)0.391
Clinical presentation
 Headache2225/279(80.6%)333/436(76.4%)0.179
 Focal deficit1111/279(39.8%)169/437(38.7%)0.766
 Seizure163/279(22.6%)109/437(24.9%)0.471
 Coma*15/279(1.8%)8/437(1.8%)1.000
Platelet count (mean SD)15269.8±93.9269.8±102.80.994
One or more positive antiphospholipid antibody11116/235(6.8%)45/371(12.1%)0.034
Factor V and prothrombin mutation18924/201(11.9%)31/327(9.5%)0.369
Imaging findings
 Venous infarct469/279(24.7%)128/434(29.5%)0.165
 Cerebral edema479/279(28.3%)129/434(29.7%)0.686
 Intracranial hemorrhage5105/278(37.8%)158/434(36.4%)0.713
Heparin infusion0214/279(76.7%)333/438(76.0%)0.836
Low molecular weight heparin093/279(33.3%)341/438(77.9%)<0.001
Endovascular treatment025/279(9.0%)28/438(6.4%)0.200
Neurosurgical treatment014/279(5.0%)19/438(4.3%)0.672
Duration of oral anticoagulation (median IQR)0194 (107–371)202.5 (120–402)0.459
Duration of treatment to imaging†182170 (88.5–257.5)178 (90–309)0.269
Duration of follow-up (median IQR)0308 (134–666)307(130–718)0.469
% and n with at least 90 days follow-up0238/279(85.3%)357/438(81.5%)0.187
DOAC indicates direct oral anticoagulants; IQR, interquartile range; and VTE, venous thromboembolism.
*
Fisher exact test was performed instead.
†
Imaging used for the recanalization analysis

Association Between Oral Anticoagulation Type and Recurrent Venous Thrombosis

Figure 2 shows the 1-year Kaplan Meier survival analysis for recurrent venous thrombosis. Recurrent venous thrombosis during follow-up occurred in 5.26 per 100 patient-years on DOAC versus 5.87 per 100 patient years on warfarin (N=845, P=0.61). In unadjusted Cox-regression analyses, DOAC treatment was associated with a similar rate of recurrent VTE as warfarin treatment (hazard ratio [HR], 0.86 [95% CI, 0.47–1.56]; P=0.61). This finding remained unchanged after IPTW without adjustment (HR, 0.94 [95% CI, 0.50–1.74]; P=0.84), adjustment for prespecified variables (aHR, 0.94 [95% CI, 0.50–1.77]; P=0.86; model 1; Table 2) or variables that differed between the 2 groups (aHR, 0.94 [95% CI, 0.51–1.73]; P=0.84; model 2; Table 2).
Table 2. Associations Between DOAC Versus Warfarin and Recurrent Venous Thrombosis, Major Hemorrhage, and Recanalization
 UnadjustedWeighted unadjustedWeighted model 1Weighted model 2Propensity matched*
Recurrent venous thrombosisN=845N=721N=721N=721N=721
HR, 0.86 (95% CI, 0.47–1.56); P=0.61HR, 0.94 (95% CI, 0.50–1.74); P=0.84HR, 0.94 (95% CI, 0.50–1.77); P=0.86HR, 0.94 (95% CI, 0.51–1.73); P=0.84HR, 0.95 (95% CI, 0.48–1.87); P=0.88
Major hemorrhageN=845N=720N=720N=720N=720
HR, 0.47 (95% CI, 0.21–1.04); P=0.06HR, 0.34 (95% CI, 0.14–0.80); P=0.01HR, 0.34 (95% CI, 0.15–0.80); P=0.01HR, 0.35 (95% CI, 0.15–0.82); P=0.02HR, 0.42 (95% CI, 0.16–1.06); P=0.07
DeathN=845N=720N=720N=720N=720
HR, 1.02 (95% CI, 0.36 –2.84); P=0.97HR, 0.66 (95% CI, 0.22–2.02); P=0.47†HR, 0.75 (95% CI, 0.21–2.70); P=0.66HR, 0.78 (95% CI, 0.22–2.76); P=0.70HR, 0.97 (95% CI, 0.31 –2.99); P=0.95
Partial/complete recanalizationN=525N=448N=448N=448N=448
OR, 1.16 (95% CI, 0.70–1.94); P=0.56OR, 0.88 (95% CI, 0.49–1.60); P=0.69OR, 0.93 (95% CI, 0.47–1.83); P=0.83OR, 0.92 (95% CI, 0.48–1.73); P=0.79OR, 0.59 (95% CI, 0.26–1.32); P=0.20
Recurrent venous thrombosis: model 1 is adjusted for age, sex, history of prior VTE, one or more positive antiphospholipid antibody; model 2: adjusted for age, sex, history of prior VTE, one or more positive antiphospholipid antibody, and low molecular weight heparin use. Major hemorrhage and death: model 1 is adjusted for age, sex, intracranial hemorrhage at baseline, and deep CVT location; model 2 is adjusted for adjusted for age, sex, intracranial hemorrhage at baseline, deep CVT location, history of prior VTE, one or more positive antiphospholipid antibody, and low molecular weight heparin use. Partial complete recanalization: model 1 is adjusted for age, sex, intracranial hemorrhage at baseline, duration of anticoagulation therapy prior to repeat imaging, and deep CVT location; model 2 is adjusted for age, sex, intracranial hemorrhage at baseline, duration of anticoagulation therapy prior to repeat imaging, deep CVT location, history of prior VTE, one or more positive antiphospholipid antibody, and low molecular weight heparin us. Propensity matched models were adjusted for variables included in model 2 for each outcome
*
Propensity matching with replacement, caliper 0.05.
†
Parametric survival analysis was used as proportionality was not met per Schoenfeld residuals.
Figure 2. One-y Kaplan Meier survival analysis during follow-up. Recurrent venous thrombosis (left), major hemorrhage (right), and death (bottom). Patients were included at the time of initiation of oral anticoagulation and were censored at the time of the event of interest, death, lost to follow-up, or discontinuation/switch anticoagulant therapy. DOAC indicates direct oral anticoagulants.

Association Between Oral Anticoagulation Type and Major Hemorrhage

Figure 2 shows the 1-year Kaplan Meier survival analysis for major hemorrhage. Major hemorrhage occurred in 2.44 per 100 patient-years on DOAC versus 4.70 per 100 patient years on warfarin (N=845, P=0.06). Intracranial hemorrhage occurred in 1.52 per 100 patient-years on DOAC versus 3.51 per 100 patient years on warfarin (N=845, P=0.05) and extracranial hemorrhage occurred in 0.91 per 100 patient-years on DOAC versus 1.15 per 100 patient years on warfarin (N=845, P=0.64). In unadjusted nonweighted Cox-regression analyses, DOAC treatment was associated with a marginally lower risk of major hemorrhage as compared with warfarin treatment (HR, 0.47 [95% CI, 0.21–1.04]; P=0.06). This finding became significant using IPTW without adjustment (HR, 0.34 [95% CI, 0.14–0.80]; P=0.01), adjustment for prespecified variables (aHR, 0.34 [95% CI, 0.15–0.80]; P=0.01; model 1; Table 2), and variables that differed between the 2 groups (aHR, 0.35 [95% CI, 0.15–0.82]; P=0.02; model 2; Table 2).
In sensitivity analysis excluding asymptomatic intracranial hemorrhage from the major hemorrhage outcomes and in the fully adjusted model (model 2), DOAC treatment was associated with a lower risk of major hemorrhage when compared with warfarin (N=720; aHR, 0.40 [95% CI, 0.16–0.995]; P=0.049).

Association Between Oral Anticoagulation Type and Death

Figure 2 shows the 1-year Kaplan Meier survival analysis for death. Death during follow-up occurred in 1.81 per 100 patient-years on DOAC versus 1.90 per 100 patient years on warfarin (N=845, P=0.97). In unadjusted nonweighted Cox regression analyses, DOAC treatment was associated with similar risk of death as warfarin treatment (HR, 1.02 [95% CI, 0.36–2.84]; P=0.97). This finding remained unchanged after IPTW, without adjustment (HR, 0.66 [95% CI, 0.22–2.02]; P=0.47), and after adjusting for prespecified variables (aHR, 0.75 [95% CI, 0.21–2.70]; P=0.66; model 1; Table 2) and variables that differed between the 2 groups (aHR, 0.78 [95% CI, 0.22–2.76]; P=0.70; model 2; Table 2).

Association Between Oral Anticoagulation Type and Venous Recanalization

Partial or complete recanalization occurred in 154 (86.0%) patients on DOAC versus 291 (84.1%) patients on warfarin (P=0.56). In unadjusted nonweighted binary-regression analyses DOAC treatment was associated with a similar rate of complete/partial recanalization as warfarin treatment (odds ratio [OR], 1.16 [95% CI, 0.70–1.94]; P=0.56). This finding remained unchanged after IPTW when unadjusted (OR, 0.88 [95% CI, 0.49–1.60]; P=0.69), adjusted for prespecified variables (aOR, 0.93 [95% CI, 0.47–1.83]; P=0.83; model 1; Table 2) and variables that differed between the 2 groups (aOR, 0.92 [95% CI, 0.48–1.73]; P=0.79; model 2; Table 2).

Propensity Score Matching

Propensity score matching with replacement included 721 patients for primary outcome analysis, 720 patients for safety outcome and for death analyses, and 448 patients for recanalization outcome. In these analyses, DOAC treatment was associated with a similar risk of recurrent venous thrombosis (aHR, 0.95 [95% CI, 0.48–1.87]; P=0.88), death (aHR, 0.97 [95% CI, 0.31–2.99]; P=0.95), partial/complete recanalization (aOR, 0.59 [95% CI, 0.26–1.32]; P=0.20), and nonsignificantly lower risk of major hemorrhage (aHR, 0.42 [95% CI, 0.16–1.06]; P=0.07) as compared with warfarin treatment (Table 2). Using propensity score matching without replacement, the findings were similar for all outcomes: recurrent venous thrombosis (N=534; aHR, 0.72 [95% CI, 0.32–1.58]; P=0.41), major hemorrhage (N=532; aHR, 0.34 [95% CI, 0.12–0.95]; P=0.04), death (N=532; aHR, 0.83 [95% CI, 0.18–3.78]; P=0.81), and recanalization outcome (N=182; aHR, 1.47 [95% CI, 0.57–3.78]; P=0.43).

Sensitivity Analyses

Since deep venous involvement and baseline hemorrhage are not well-established predictors of recanalization and major hemorrhage, we performed sensitivity analyses excluding them from models 1 and 2. In these analyses, DOAC treatment was associated with similar partial or complete recanalization rates: model 1 (N=449; aOR, 0.87 [95% CI, 0.46–1.64]; P=0.66) and model 2 (N=449; aOR, 0.87 [95% CI, 0.47–1.59]; P=0.64), but lower risk of major hemorrhage during follow-up: model 1 (N=721; aHR, 0.34 [95% CI, 0.15–0.81]; P=0.01) and model 2 (N=721; aHR, 0.35 [95% CI, 0.15–0.81]; P=0.02).
In addition, since the presence of one or more positive antiphospholipid antibodies is not a known predictor of venous thrombosis recurrence and was not routinely performed on patients in our study, we performed sensitivity analyses excluding this variable from models 1 and 2 of recurrent venous thrombosis outcome. In these analyses, DOAC treatment was associated with similar recurrent venous thrombosis rate: model 1 (N=845; aHR, 0.86 [95% CI, 0.49–1.49]; P=0.59) and model 2 (N=845; aHR, 0.85 [95% CI, 0.49–1.45]; P=0.55). Moreover, since the time of CVT recurrence may be a proxy for the CVT recurrence mechanism (extension versus de novo), we compared the 2 treatments with respect to recurrent CVT occurring within 90 days from oral anticoagulation initiation versus those occurring beyond 90 days from oral anticoagulation initiation. In these analyses using the fully adjusted IPTW model (model 2), DOAC was associated with a similar rate of CVT recurrence in the first 90 days (N=721; aHR, 1.13 [95% CI, 0.44–2.87]; P=0.80) versus beyond 90 days (N=721; aHR, 0.94 [95% CI, 0.33–2.72]; P=0.91). Using 2-week and 4-week cutoffs yielded similar findings.
Furthermore, we performed sensitivity analyses excluding patients who were event free of the outcome of interest but were lost to follow-up prior to 90 days. In these analyses and fully adjusted models (model 2), DOAC treatment was associated with a similar risk of recurrent venous thrombosis (N=623; aHR, 0.91 [95% CI, 0.50–1.67]; P=0.76), death (N=620; aHR, 0.69 [95% CI, 0.23–2.04]; P=0.50), and partial/complete recanalization (N=419; aOR, 0.91 [95% CI, 0.46–1.79]; P=0.79) but a lower risk of major hemorrhage (N=622; aHR, 0.33 [95% CI, 0.14–0.78]; P=0.01).
Finally, since part of the study was conducted during the COVID-19 pandemic, our study included patients with CVT in the setting of COVID-19 (n=6 patients). When such patients were excluded in sensitivity analyses, the findings remained unchanged.

Discussion

This large, multicenter, international, retrospective, observational study found that, in a real-world cohort of patients diagnosed with CVT, DOAC treatment was associated with a similar risk of VTE recurrence, death, and CVT recanalization rates but a lower risk of major hemorrhage, as compared with warfarin treatment. These findings are consistent with other studies showing similar efficacy but improved safety with DOACs compared with warfarin.24–26 Our findings are concordant with the RESPECT-CVT trial as well as systematic reviews and meta-analyses of small observational studies that suggested comparable outcomes with DOACs versus warfarin in patients with CVT.10,27–29 Importantly, in contrast to previous studies,10,27–29 we observed a reduced risk of major hemorrhage with DOACs compared with warfarin.
The goals of anticoagulation in patients with CVT are to reduce the risk of recurrent venous thrombosis, CVT extension, death, and achieve cerebral venous recanalization. Consistent with prior studies of VTE3–6 or CVT,10,27–29 we observed a comparable risk of recurrent venous thrombosis and death in patients treated with warfarin versus DOACs. A further important goal in the management of patients with CVT is to promote recanalization, as it has been shown that lack of recanalization is associated with long-term morbidity including chronic headaches.30 Arguably, recanalization aids in renormalizing elevated intracranial pressure and thus attenuates the risk of vision loss and chronic papilledema, as well as the development of a dural arterio-venous fistula due to persistent elevation in venous pressure. Similar to others,10,27–29,31 we found similar recanalization rates in patients treated with DOAC versus warfarin treatment. It is also important to note that the recurrent CVT outcome in our study included progression of thrombosis while on oral anticoagulation. This is a clinically important outcome because thrombosis progression may lead to neurological deterioration, increased intracranial pressure, venous infarction, and promote intracerebral hemorrhage. This rate was captured in dabigatran treated patients in the RESPECT-CVT trial and was 1.7%,10 which may possibly explain the difference between our recurrent CVT rate and that in prior observational studies.
The favorable safety profile of DOACs over warfarin in our study is consistent with data from non-CVT patient populations. For example, in patients with atrial fibrillation, apixaban has comparable risk of extracranial hemorrhage but lower risk of overall major and intracranial hemorrhage when compared with warfarin.25 Rivaroxaban and dabigatran had similar rates of major and clinically relevant bleeding when compared with warfarin but lower risk of intracranial hemorrhage.24,26 Furthermore, in patients with VTE, apixaban has been shown to have similar efficacy in recurrence VTE risk reduction but reduced risk of hemorrhagic complications when compared with warfarin.4 Additionally, a posthoc analysis of the RE-COVER and RE-COVER II trials (Efficacy and Safety of Dabigatran compared With Warfarin for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism) showed similar risk of recurrent VTE or VTE-related mortality but reduced major hemorrhage in patients treated with dabigatran when compared with warfarin.32 Interestingly, the improved safety of dabigatran over warfarin was only seen in younger patients, which more closely resembles the age group studied in our population.32 An important challenge to consider about intracranial hemorrhage in the setting of CVT is that new or worsening hemorrhage may have been linked to progression of thrombosis and thus may be more linked to treatment efficacy as opposed to safety.
Our study supports current evidence that DOACs represent a reasonable alternative to warfarin in patients with CVT. Although DOACs do not require blood level monitoring, they generally are more expensive than warfarin. Thus, further studies are needed to test whether the improved safety profile of DOACs is cost-effective. Several studies suggest that DOACs offer a cost-effective alternative for patients with atrial fibrillation and those with VTE,33,34 however, cost analyses are lacking for patients with CVT. Nevertheless, it is expected that once patent protection for DOACs expires more affordable generic drugs will become available.
Our study has several limitations inherent to its retrospective, observational design, and noncentral and nonblinded determination and adjudication of clinical and imaging outcomes. While we compared baseline characteristics between the 2 groups and included propensity score adjustment and matching, we cannot exclude the possibility of residual treatment-by-indication bias. Second, 15.7% of patients were lost to follow-up within 90-days. However, the baseline characteristics were overall similar between the patients with versus without at least 90-day follow-up, assuaging concerns about major attrition bias. Third, the low event rate of recurrent VTE in our study, which is consistent with other studies,10,19,35 may have left us underpowered to show a difference between the 2 groups and precluded us from conducting detailed subgroup analyses. For example, CVT is a heterogenous disease for which it remains uncertain whether one treatment strategy may be better than the other in certain sub-populations. Fourth, recurrent CVT in our study included both de novo CVT as well as CVT extension. This may at least partially explain the higher recurrent CVT rates in our studies compared with others. While both are important outcomes to capture, we are unable to distinguish between the two with certainty in our study and thus it remains unknown if one treatment is superior to the other with respect to each of these outcomes. Fifth, we did not have data on international normalized ratio levels in warfarin treated patients and thus some recurrence of venous thrombosis and major hemorrhage events may have been in the setting of subtherapeutic or supratherapeutic anticoagulation. This, however, reflects a true real-world experience in patients treated with warfarin. Sixth, the rate of asymptomatic hemorrhage in our study was likely low due to ascertainment bias since asymptomatic patients do not typically undergo follow-up brain imaging. Finally, the timing of follow-up imaging was heterogeneous among patients, limiting our recanalization status analysis.

Conclusions

Our findings provide real-world data supporting the use of DOACs as a reasonable alternative to warfarin treatment in patients with CVT. Given the study limitations, our findings should be interpreted with caution and require confirmation by large prospective observational studies such as the DOAC-CVT study (Direct Oral Anticoagulants in the Treatment of Cerebral Venous Thrombosis; https://clinicaltrials.gov; NCT04660747) and the ongoing randomized SECRET trial (Study of Rivaroxaban for Cerebral Venous Thrombosis; https://clinicaltrials.gov; NCT03178864).

Article Information

Supplemental Material

STROBE Checklist
Figure S1
Table S1

Footnote

Nonstandard Abbreviations and Acronyms

ACTION-CVT
Anticoagulation in the Treatment of Cerebral Venous Thrombosis
CVT
cerebral venous thrombosis
DOAC
direct oral anticoagulants
HR
hazard ratio
IPTW
inverse probability of treatment weighted
OR
odds ratio
RESPECT-CVT
A Clinical Trial Comparing Efficacy and Safety of Dabigatran Etexilate With Warfarin in Patients With Cerebral Venous and Dural Sinus Thrombosis
VTE
venous thromboembolism

Supplemental Material

File (str_stroke-2021-037541_supp1.pdf)

References

1.
Bousser MG, Ferro JM. Cerebral venous thrombosis: an update. Lancet Neurol. 2007;6:162–170. doi: 10.1016/S1474-4422(07)70029-7
Crossref
PubMed
Google Scholar
2.
Saposnik G, Barinagarrementeria F, Brown RD, Bushnell CD, Cucchiara B, Cushman M, deVeber G, Ferro JM, Tsai FY; American Heart Association Stroke Council and the Council on Epidemiology and Prevention. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42:1158–1192. doi: 10.1161/STR.0b013e31820a8364
Crossref
PubMed
Google Scholar
3.
Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406–1415. doi: 10.1056/NEJMoa1306638
Crossref
PubMed
Google Scholar
4.
Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799–808. doi: 10.1056/NEJMoa1302507
Crossref
PubMed
Google Scholar
5.
Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499–2510
Crossref
PubMed
Google Scholar
6.
Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342–2352. doi: 10.1056/NEJMoa0906598
Crossref
PubMed
Google Scholar
7.
Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman M, King CS, Morris TA, Sood N, et al. Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149:315–352. doi: 10.1016/j.chest.2015.11.026
Crossref
PubMed
Google Scholar
8.
Osteresch R, Fach A, Hambrecht R, Wienbergen H. [ESC guidelines 2019 on diagnostics and management of acute pulmonary embolism]. Herz. 2019;44:696–700. doi: 10.1007/s00059-019-04863-5
Crossref
Google Scholar
9.
Ortel TL, Neumann I, Ageno W, Beyth R, Clark NP, Cuker A, Hutten BA, Jaff MR, Manja V, Schulman S, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv. 2020;4:4693–4738. doi: 10.1182/bloodadvances.2020001830
Crossref
PubMed
Google Scholar
10.
Ferro JM, Coutinho JM, Dentali F, Kobayashi A, Alasheev A, Canhão P, Karpov D, Nagel S, Posthuma L, Roriz JM, et al; RE-SPECT CVT Study Group. Safety and efficacy of dabigatran etexilate vs dose-adjusted warfarin in patients with cerebral venous thrombosis: a randomized clinical trial. JAMA Neurol. 2019;76:1457–1465. doi: 10.1001/jamaneurol.2019.2764
Crossref
PubMed
Google Scholar
11.
Silvis SM, Middeldorp S, Zuurbier SM, Cannegieter SC, Coutinho JM. Risk factors for cerebral venous thrombosis. Semin Thromb Hemost. 2016;42:622–631. doi: 10.1055/s-0036-1584132
Crossref
PubMed
Google Scholar
12.
Liberman AL, Merkler AE, Gialdini G, Messé SR, Lerario MP, Murthy SB, Kamel H, Navi BB. Risk of pulmonary embolism after cerebral venous thrombosis. Stroke. 2017;48:563–567. doi: 10.1161/STROKEAHA.116.016316
Crossref
PubMed
Google Scholar
13.
Liberman AL, Kamel H, Mullen MT, Messé SR. International classification of diseases, Ninth Revision (ICD-9) diagnosis codes can identify cerebral venous thrombosis in hospitalized adults. Neurohospitalist. 2016;6:147–150. doi: 10.1177/1941874416648198
Crossref
PubMed
Google Scholar
14.
Handley JD, Emsley HC. Validation of ICD-10 codes shows intracranial venous thrombosis incidence to be higher than previously reported. Health Inf Manag. 2020;49:58–61. doi: 10.1177/1833358318819105
Crossref
Google Scholar
15.
Sayar Z, Moll R, Isenberg D, Cohen H. Thrombotic antiphospholipid syndrome: A practical guide to diagnosis and management. Thromb Res. 2021;198:213–221. doi: 10.1016/j.thromres.2020.10.010
Crossref
Google Scholar
16.
Lyman GH, Carrier M, Ay C, Di Nisio M, Hicks LK, Khorana AA, Leavitt AD, Lee AYY, Macbeth F, Morgan RL, et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Blood Adv. 2021;5:927–974. doi: 10.1182/bloodadvances.2020003442
Crossref
PubMed
Google Scholar
17.
Bates SM, Greer IA, Hirsh J, Ginsberg JS. Use of antithrombotic agents during pregnancy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(Suppl 3):627S–644S. doi: 10.1378/chest.126.3_suppl.627S
Crossref
Google Scholar
18.
Miranda B, Ferro JM, Canhão P, Stam J, Bousser MG, Barinagarrementeria F, Scoditti U; ISCVT Investigators. Venous thromboembolic events after cerebral vein thrombosis. Stroke. 2010;41:1901–1906. doi: 10.1161/STROKEAHA.110.581223
Crossref
PubMed
Google Scholar
19.
Palazzo P, Agius P, Ingrand P, Ciron J, Lamy M, Berthomet A, Cantagrel P, Neau JP. Venous thrombotic recurrence after cerebral venous thrombosis: a long-term follow-up study. Stroke. 2017;48:321–326. doi: 10.1161/STROKEAHA.116.015294
Crossref
PubMed
Google Scholar
20.
Girot M, Ferro JM, Canhão P, Stam J, Bousser MG, Barinagarrementeria F, Leys D; ISCVT Investigators. Predictors of outcome in patients with cerebral venous thrombosis and intracerebral hemorrhage. Stroke. 2007;38:337–342. doi: 10.1161/01.STR.0000254579.16319.35
Crossref
PubMed
Google Scholar
21.
Klok FA, Kooiman J, Huisman MV, Konstantinides S, Lankeit M. Predicting anticoagulant-related bleeding in patients with venous thromboembolism: a clinically oriented review. Eur Respir J. 2015;45:201–210. doi: 10.1183/09031936.00040714
Crossref
Google Scholar
22.
Aguiar de Sousa D, Lucas Neto L, Canhão P, Ferro JM. Recanalization in cerebral venous thrombosis. Stroke. 2018;49:1828–1835.
Crossref
PubMed
Google Scholar
23.
Aguiar de Sousa D, Lucas Neto L, Arauz A, Sousa AL, Gabriel D, Correia M, Gil-Gouveia R, Penas S, Carvalho Dias M, Correia MA, et al. Early recanalization in patients with cerebral venous thrombosis treated with anticoagulation. Stroke. 2020;51:1174–1181.
Crossref
PubMed
Google Scholar
24.
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–891. doi: 10.1056/NEJMoa1009638
Crossref
PubMed
Google Scholar
25.
Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–992. doi: 10.1056/NEJMoa1107039
Crossref
PubMed
Google Scholar
26.
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–1151. doi: 10.1056/NEJMoa0905561
Crossref
PubMed
Google Scholar
27.
Bose G, Graveline J, Yogendrakumar V, Shorr R, Fergusson DA, Le Gal G, Coutinho J, Mendonça M, Viana-Baptista M, Nagel S, et al. Direct oral anticoagulants in treatment of cerebral venous thrombosis: a systematic review. BMJ Open. 2021;11:e040212. doi: 10.1136/bmjopen-2020-040212
Crossref
Google Scholar
28.
Nepal G, Kharel S, Bhagat R, Ka Shing Y, Ariel Coghlan M, Poudyal P, Ojha R, Sunder Shrestha G. Safety and efficacy of Direct Oral Anticoagulants in cerebral venous thrombosis: a meta-analysis. Acta Neurol Scand. 2022;145:10–23. doi: 10.1111/ane.13506
Crossref
Google Scholar
29.
Lee GKH, Chen VH, Tan CH, Leow AST, Kong WY, Sia CH, Chew NWS, Tu TM, Chan BPL, Yeo LLL, et al. Comparing the efficacy and safety of direct oral anticoagulants with vitamin K antagonist in cerebral venous thrombosis. J Thromb Thrombolysis. 2020;50:724–731. doi: 10.1007/s11239-020-02106-7
Crossref
Google Scholar
30.
Ji K, Zhou C, Wu L, Li W, Jia M, Chu M, Wu D, Hou C, Duan J, Meng R, et al. Risk factors for severe residual headache in cerebral venous thrombosis. Stroke. 2021;52:531–536. doi: 10.1161/STROKEAHA.120.029820
Crossref
PubMed
Google Scholar
31.
Cheung YW, Middeldorp S, Prins MH, Pap AF, Lensing AW, Ten Cate-Hoek AJ, Villalta S, Milan M, Beyer-Westendorf J, Verhamme P, et al; Einstein PTS Investigators Group. Post-thrombotic syndrome in patients treated with rivaroxaban or enoxaparin/vitamin K antagonists for acute deep-vein thrombosis. A post-hoc analysis. Thromb Haemost. 2016;116:733–738. doi: 10.1160/TH16-01-0041
Crossref
Google Scholar
32.
Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, et al; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129:764–772. doi: 10.1161/CIRCULATIONAHA.113.004450
Crossref
PubMed
Google Scholar
33.
Al Mukdad M, Al-Badriyeh D, Elewa HF. Cost-effectiveness evaluations among the direct oral anticoagulants for the prevention and treatment of venous thromboembolism: systematic review. Clin Appl Thromb Hemost. 2019;25:1076029619849103. doi: 10.1177/1076029619849103
Crossref
Google Scholar
34.
Lorenzoni V, Pirri S, Turchetti G. Cost-effectiveness of direct non-vitamin K oral anticoagulants versus vitamin K antagonists for the management of patients with non-valvular atrial fibrillation based on available “Real-World” evidence: the Italian National Health System Perspective. Clin Drug Investig. 2021;41:255–267. doi: 10.1007/s40261-021-01002-z
Crossref
Google Scholar
35.
Dentali F, Poli D, Scoditti U, Di Minno MN, De Stefano V, Stefano VD, Siragusa S, Kostal M, Palareti G, Sartori MT, et al; CErebral VEin Thrombosis International Study Investigators. Long-term outcomes of patients with cerebral vein thrombosis: a multicenter study. J Thromb Haemost. 2012;10:1297–1302. doi: 10.1111/j.1538-7836.2012.04774.x
Crossref
PubMed
Google Scholar

eLetters(0)

eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.

Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.

Sign In to Submit a Response to This Article

Information & Authors

Information

Published In

Go to Stroke
Stroke
Volume 53 • Number 3 • March 2022
Pages: 728 - 738
PubMed: 35143325

Copyright

© 2022 American Heart Association, Inc.

Versions

You are viewing the most recent version of this article.

History

Received: 4 October 2021
Revision received: 7 January 2022
Accepted: 12 January 2022
Published online: 10 February 2022
Published in print: March 2022

Permissions

Request permissions for this article.

Keywords

  1. anticoagulants
  2. contraindications
  3. dabigatran
  4. hemorrhage
  5. venous thrombosis

Subjects

  1. Cerebrovascular Disease/Stroke

Authors

Affiliations

Shadi Yaghi, MD https://orcid.org/0000-0003-0031-1004 [email protected]
Department of Neurology, Brown University, Providence, RI (S.Y., L.S., C.S., N.K., S.E.J., A.C., S.C., K.F.).
View all articles by this author
Liqi Shu, MD https://orcid.org/0000-0002-9784-8475
Department of Neurology, Brown University, Providence, RI (S.Y., L.S., C.S., N.K., S.E.J., A.C., S.C., K.F.).
View all articles by this author
Ekaterina Bakradze, MD https://orcid.org/0000-0001-7534-7218
Department of Neurology, University of Alabama at Birmingham (E.B.).
View all articles by this author
Setareh Salehi Omran, MD https://orcid.org/0000-0002-3184-5327
Department of Neurology, University of Colorado School of Medicine, Aurora (S.S.O.).
View all articles by this author
James A. Giles, MD https://orcid.org/0000-0002-3197-3062
Department of Neurology, Washington University, Saint Louis, MO (J.A.G., J.Y.A.).
View all articles by this author
Jordan Y. Amar, MD
Department of Neurology, Washington University, Saint Louis, MO (J.A.G., J.Y.A.).
View all articles by this author
Nils Henninger, MD, PhD, Dr med https://orcid.org/0000-0002-3883-5623
Department of Neurology (N.H., M.E.), University of Massachusetts, Worcester.
Department of Psychiatry (N.H.), University of Massachusetts, Worcester.
View all articles by this author
Marwa Elnazeir, MD
Department of Neurology (N.H., M.E.), University of Massachusetts, Worcester.
View all articles by this author
Ava L. Liberman, MD https://orcid.org/0000-0003-0184-6035
Department of Neurology, Weill Cornell Medical Center, NY (A.L.L.).
View all articles by this author
Khadean Moncrieffe, BS https://orcid.org/0000-0002-2310-4609
Department of Neurology, Montefiore Medical Center, NY (K.M., J.L.).
View all articles by this author
Jenny Lu, BS https://orcid.org/0000-0002-4259-5677
Department of Neurology, Montefiore Medical Center, NY (K.M., J.L.).
View all articles by this author
Richa Sharma, MD https://orcid.org/0000-0003-0798-2353
Department of Neurology, Yale University, New Haven, CT (R.S., Y.C., A.S.Z., A.d.H.).
View all articles by this author
Yee Cheng, MD
Department of Neurology, Yale University, New Haven, CT (R.S., Y.C., A.S.Z., A.d.H.).
View all articles by this author
Adeel S. Zubair, MD
Department of Neurology, Yale University, New Haven, CT (R.S., Y.C., A.S.Z., A.d.H.).
View all articles by this author
Alexis N. Simpkins, MD, PhD, MSCR https://orcid.org/0000-0001-7529-4267
Department of Neurology, University of Florida, Gainesville (A.N.S., G.T.L., J.C.K., D.P.).
View all articles by this author
Grace T. Li, MD https://orcid.org/0000-0001-9983-2672
Department of Neurology, University of Florida, Gainesville (A.N.S., G.T.L., J.C.K., D.P.).
View all articles by this author
Justin Chi Kung, BS https://orcid.org/0000-0002-1382-2711
Department of Neurology, University of Florida, Gainesville (A.N.S., G.T.L., J.C.K., D.P.).
View all articles by this author
Dezaray Perez, BS https://orcid.org/0000-0003-4060-3001
Department of Neurology, University of Florida, Gainesville (A.N.S., G.T.L., J.C.K., D.P.).
View all articles by this author
Mirjam Heldner, MD https://orcid.org/0000-0002-3594-2159
Department of Neurology, Inselspital Universitätsspital, Bern, Switzerland (M.H., A.S., D.S., B.S.).
View all articles by this author
Adrian Scutelnic, MD https://orcid.org/0000-0001-9053-584X
Department of Neurology, Inselspital Universitätsspital, Bern, Switzerland (M.H., A.S., D.S., B.S.).
View all articles by this author
David Seiffge, MD https://orcid.org/0000-0003-3890-3849
Department of Neurology, Inselspital Universitätsspital, Bern, Switzerland (M.H., A.S., D.S., B.S.).
View all articles by this author
Bernhard Siepen, MD
Department of Neurology, Inselspital Universitätsspital, Bern, Switzerland (M.H., A.S., D.S., B.S.).
View all articles by this author
Aaron Rothstein, MD https://orcid.org/0000-0002-8480-8220
Department of Neurology, University of Pennsylvania, Philadelphia, PA (A.R., O.K., D.D.).
View all articles by this author
Ossama Khazaal, MD https://orcid.org/0000-0002-8308-6596
Department of Neurology, University of Pennsylvania, Philadelphia, PA (A.R., O.K., D.D.).
View all articles by this author
David Do, MD https://orcid.org/0000-0003-3604-5609
Department of Neurology, University of Pennsylvania, Philadelphia, PA (A.R., O.K., D.D.).
View all articles by this author
Sami Al Kasab, MD https://orcid.org/0000-0001-8909-9761
Department of Neurology (S.A.K., L.A.R.), Medical University of South Carolina, Charleston.
Department of Neurosurgery (S.A.K.), Medical University of South Carolina, Charleston.
View all articles by this author
Line Abdul Rahman, MD https://orcid.org/0000-0002-6660-032X
Department of Neurology (S.A.K., L.A.R.), Medical University of South Carolina, Charleston.
View all articles by this author
Eva A. Mistry, MD https://orcid.org/0000-0002-7426-3650
Department of Neurology and Rehabilitation Medicine, University of Cincinnati (E.A.M., P.K., Y.A., B.C.).
View all articles by this author
Deborah Kerrigan, MD https://orcid.org/0000-0002-1722-6677
Department of Neurology, Vanderbilt University, Nashville, TN (D.K., H.L.).
View all articles by this author
Hayden Lafever, BS
Department of Neurology, Vanderbilt University, Nashville, TN (D.K., H.L.).
View all articles by this author
Thanh N. Nguyen, MD https://orcid.org/0000-0002-2810-1685
Department of Neurology, Boston University School of Medicine, MA (T.N.N., P.K., H.A.).
View all articles by this author
Piers Klein https://orcid.org/0000-0001-7468-137X
Department of Neurology and Rehabilitation Medicine, University of Cincinnati (E.A.M., P.K., Y.A., B.C.).
Department of Neurology, Boston University School of Medicine, MA (T.N.N., P.K., H.A.).
View all articles by this author
Hugo Aparicio, MD https://orcid.org/0000-0001-8584-1455
Department of Neurology, Boston University School of Medicine, MA (T.N.N., P.K., H.A.).
View all articles by this author
Jennifer Frontera, MD https://orcid.org/0000-0002-0719-2522
Department of Neurology, New York University, NY (J.F., L.K., S.A.).
View all articles by this author
Lindsey Kuohn, BS https://orcid.org/0000-0001-9500-6162
Department of Neurology, New York University, NY (J.F., L.K., S.A.).
View all articles by this author
Shashank Agarwal, MD https://orcid.org/0000-0001-5097-416X
Department of Neurology, New York University, NY (J.F., L.K., S.A.).
View all articles by this author
Christoph Stretz, MD https://orcid.org/0000-0003-4125-4077
Department of Neurology, Brown University, Providence, RI (S.Y., L.S., C.S., N.K., S.E.J., A.C., S.C., K.F.).
View all articles by this author
Narendra Kala, MD
Department of Neurology, Brown University, Providence, RI (S.Y., L.S., C.S., N.K., S.E.J., A.C., S.C., K.F.).
View all articles by this author
Sleiman El Jamal, MD https://orcid.org/0000-0002-4732-0170
Department of Neurology, Brown University, Providence, RI (S.Y., L.S., C.S., N.K., S.E.J., A.C., S.C., K.F.).
View all articles by this author
Alison Chang, BS
Department of Neurology, Brown University, Providence, RI (S.Y., L.S., C.S., N.K., S.E.J., A.C., S.C., K.F.).
View all articles by this author
Shawna Cutting, MD https://orcid.org/0000-0002-0072-7248
Department of Neurology, Brown University, Providence, RI (S.Y., L.S., C.S., N.K., S.E.J., A.C., S.C., K.F.).
View all articles by this author
Han Xiao, MPH https://orcid.org/0000-0002-6770-7700
Department of Biostatistics, University of California Santa Barbara (H.X.).
View all articles by this author
Adam de Havenon, MD https://orcid.org/0000-0001-8178-8597
Department of Neurology, Yale University, New Haven, CT (R.S., Y.C., A.S.Z., A.d.H.).
View all articles by this author
Varsha Muddasani, MD https://orcid.org/0000-0002-4225-8558
Department of Neurology, University of Utah, Salt Lake City (V.M.).
View all articles by this author
Teddy Wu, MD https://orcid.org/0000-0003-1845-1769
Department of Neurology, Christchurch hospital, New Zealand (T.W., D.W.).
View all articles by this author
Duncan Wilson, MD
Department of Neurology, Christchurch hospital, New Zealand (T.W., D.W.).
View all articles by this author
Amre Nouh, MD
Department of Neurology, Hartford Hospital, CT (A.N., S.D.A.).
View all articles by this author
Syed Daniyal Asad, MD https://orcid.org/0000-0001-9377-8353
Department of Neurology, Hartford Hospital, CT (A.N., S.D.A.).
View all articles by this author
Abid Qureshi, MD https://orcid.org/0000-0002-1498-6638
Department of Neurology, University of Kansas, Kansas City (A.Q., J.M.).
View all articles by this author
Justin Moore, MD https://orcid.org/0000-0002-6002-0455
Department of Neurology, University of Kansas, Kansas City (A.Q., J.M.).
View all articles by this author
Yasmin Aziz, MD https://orcid.org/0000-0002-3515-4005
Department of Neurology and Rehabilitation Medicine, University of Cincinnati (E.A.M., P.K., Y.A., B.C.).
View all articles by this author
Bryce Casteigne, MD https://orcid.org/0000-0002-3621-2158
Department of Neurology and Rehabilitation Medicine, University of Cincinnati (E.A.M., P.K., Y.A., B.C.).
View all articles by this author
Muhib Khan, MD https://orcid.org/0000-0001-6329-8703
Department of Neurology, Spectrum Health, Michigan State University, Grand Rapids (M.K., Y.C.).
View all articles by this author
Yao Cheng, MD
Department of Neurology, Spectrum Health, Michigan State University, Grand Rapids (M.K., Y.C.).
View all articles by this author
Brian Mac Grory, MD https://orcid.org/0000-0003-3914-8419
Department of Neurology, Duke University, Durham, NC (B.M.G., M.W., D.R.).
View all articles by this author
Martin Weiss, MD
Department of Neurology, Duke University, Durham, NC (B.M.G., M.W., D.R.).
View all articles by this author
Dylan Ryan, MD https://orcid.org/0000-0001-7254-0020
Department of Neurology, Duke University, Durham, NC (B.M.G., M.W., D.R.).
View all articles by this author
Maria Cristina Vedovati, MD
Department of Medicine and Surgery, University of Perugia, Italy (M.C.V.).
View all articles by this author
Maurizio Paciaroni, MD https://orcid.org/0000-0002-5483-8795
Neurology – Stroke Unit, IRCCS MultiMedica, Milano, Italy (M.P.).
View all articles by this author
James E. Siegler, MD https://orcid.org/0000-0003-0287-3967
Department of Neurology, Cooper University, Camden, NJ (J.E.S., S.K., S.Y.).
View all articles by this author
Scott Kamen, BS https://orcid.org/0000-0003-4473-9272
Department of Neurology, Cooper University, Camden, NJ (J.E.S., S.K., S.Y.).
View all articles by this author
Siyuan Yu, BS https://orcid.org/0000-0001-7345-8088
Department of Neurology, Cooper University, Camden, NJ (J.E.S., S.K., S.Y.).
View all articles by this author
Christopher R. Leon Guerrero, MD https://orcid.org/0000-0002-5997-5342
Department of Neurology, George Washington University, District of Columbia (C.R.L.G., E.A.).
View all articles by this author
Eugenie Atallah, MD https://orcid.org/0000-0002-5594-9059
Department of Neurology, George Washington University, District of Columbia (C.R.L.G., E.A.).
View all articles by this author
Gian Marco De Marchis, MD, MSc https://orcid.org/0000-0002-0342-9780
Department of Neurology, University Hospital Basel and University of Basel, Switzerland (G.M.D.M., T.D.).
View all articles by this author
Alex Brehm, MD https://orcid.org/0000-0002-1630-6210
Department of interventional and diagnostic Neuroradiology, Clinic of Radiology and Nuclear Medicine, University Hospital Basel and University of Basel, Switzerland (A.B., M.P.).
View all articles by this author
Tolga Dittrich, MD https://orcid.org/0000-0002-9987-3631
Department of Neurology, University Hospital Basel and University of Basel, Switzerland (G.M.D.M., T.D.).
View all articles by this author
Marios Psychogios, MD https://orcid.org/0000-0002-0016-414X
Department of interventional and diagnostic Neuroradiology, Clinic of Radiology and Nuclear Medicine, University Hospital Basel and University of Basel, Switzerland (A.B., M.P.).
View all articles by this author
Ronald Alvarado-Dyer, MD https://orcid.org/0000-0002-6902-2510
Department of Neurology, University of Chicago, IL (R.A.-D., T.K.-H., S.P.).
View all articles by this author
Tareq Kass-Hout, MD
Department of Neurology, University of Chicago, IL (R.A.-D., T.K.-H., S.P.).
View all articles by this author
Shyam Prabhakaran, MD https://orcid.org/0000-0003-0724-1694
Department of Neurology, University of Chicago, IL (R.A.-D., T.K.-H., S.P.).
View all articles by this author
Tristan Honda, BS https://orcid.org/0000-0001-9999-230X
Department of Neurology, University of California at Los Angeles (T.H., D.S.L.).
View all articles by this author
David S. Liebeskind, MD https://orcid.org/0000-0002-5109-8736
Department of Neurology, University of California at Los Angeles (T.H., D.S.L.).
View all articles by this author
Karen Furie, MD https://orcid.org/0000-0003-0065-3784
Department of Neurology, Brown University, Providence, RI (S.Y., L.S., C.S., N.K., S.E.J., A.C., S.C., K.F.).
View all articles by this author

Notes

This article was sent to Theresa A. Jones, Guest Editor, for review by expert referees, editorial decision, and final disposition.
Supplemental Material is available at Supplemental Material.
For Sources of Funding and Disclosures, see page 737.
Presented in part at the International Stroke Conference, New Orleans, LA, and virtual, February 9–11, 2022.
Correspondence to: Shadi Yaghi, MD, FAHA, Department of Neurology, Brown Medical School, 593 Eddy Street APC 5, Providence, RI 02903. Email [email protected]

Disclosures

Dr Giles reports grants from Preston M. Green Charitable Foundation and grants from American Heart Association. Dr Henninger reports employment by University of Massachusetts Medical School. Dr Li reports grants from National Institute of Health. Dr Siepen reports grants from Banger-Rhyner Foundation/Swiss Academy of Medical Sciences. Dr Nguyen reports compensation from Medtronic for other services. Dr Aparicio reports grants from American Academy of Neurology; grants from Alzheimer’s Association; and employment by Boston University. Dr de Havenon reports compensation from Integra for consultant services; grants from Regeneron Pharmaceuticals, Inc; stock options in Certus; and grants from AMAG Pharmaceuticals, Inc. Dr Nouh reports stock options in openwater and compensation from Genentech for other services. Dr Assad reports employment by Massachusetts General Hospital. Dr Khatri reports compensation from Bayer for consultant services. Dr Paciaroni reports compensation from PFIZER CANADA INC for other services; compensation from Bristol-Myers Squibb for other services; compensation from Bayer for other services; compensation from Boehringer Ingelheim for other services; and compensation from SANOFI-AVENTIS US LLC for other services. Dr Siegler reports compensation from AstraZeneca for other services and compensation from Ceribell for consultant services. Dr Marchis reports travel support from Medtronic; travel support from Pfizer; and compensation from Bayer for consultant services. Dr Prabhakaran reports compensation from AbbVie for consultant services; compensation from Wolters Klewer Health, Inc for consultant services; and compensation from National Institute of Health for other services. Dr Liebeskind reports compensation from Genentech for consultant services; compensation from Cerenovus for consultant services; compensation from Medtronic for consultant services; and compensation from Stryker for consultant services. Dr Furie reports compensation from Janssen Biotech for consultant services.Dr Khan reports research support from National Institute of Neurological Diseases and Stroke (NINDS). The other authors report no conflicts.

Sources of Funding

This work has been supported partially by Italian Ministry of Heatlh Ricerca Corrente—IRCCS MultiMedica.

Metrics & Citations

Metrics

Citations

Download Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.

    • Jheng-yan Wu,
    • Chih-cheng Lai,
    • Huey-Juan Lin,
    • Kuan-Hsien Lu,
    • Wan-Hsuan Hsu,
    • Ting-ying Chu,
    Comparing the effectiveness and safety of direct oral anticoagulants and warfarin in patients with cerebral venous thrombosis: A real-world study, Journal of Stroke and Cerebrovascular Diseases, 34, 6, (108290), (2025).https://doi.org/10.1016/j.jstrokecerebrovasdis.2025.108290
    Crossref
    • Giuseppe Miceli,
    • Anna Maria Ciaccio,
    • Antonino Tuttolomondo,
    Challenges and Opportunities of Direct Oral Anticoagulant (DOAC) Therapy in Complex Clinical Scenarios: A Comprehensive Review and Practical Guide, Journal of Clinical Medicine, 14, 9, (2914), (2025).https://doi.org/10.3390/jcm14092914
    Crossref
    • Małgorzata Wiszniewska,
    Perspective Chapter: Cerebral Venous Thrombosis – New Trends in Therapy?, Coagulation Disorders - Innovative Developments in Diagnostic and Therapeutic Approaches [Working Title], (2025).https://doi.org/10.5772/intechopen.1010110
    Crossref
    • He-Tao Bian,
    • Xia Wang,
    • Gui-You Liu,
    • Chen Zhou,
    • Ran Meng,
    • Lan Liu,
    • Jian-Gang Duan,
    • Feng Yan,
    • Chuan-Hui Li,
    • Min Li,
    • Wen Hui,
    • Xu-Xiang Zhang,
    • Dong Zhao,
    • Ya-Peng Li,
    • Qi Fang,
    • De-Zhi Kang,
    • Hong-Liang Zeng,
    • Zhi-Jian Liang,
    • Zheng-Hao Shi,
    • Wei Yue,
    • Qin-Jian Sun,
    • Gui-Sheng Chen,
    • Jian-Long Song,
    • Zhong-Rui Yan,
    • Qiu-Hong Ji,
    • Kai-Jie Wang,
    • Lu-Sha Tong,
    • Xiao Hu,
    • Wen-Feng Cao,
    • Wei Yan,
    • Rui-Jiang Gao,
    • Qi Li,
    • Jian-Yi Wang,
    • Yi Liu,
    • Bao-Jun Wang,
    • Xiao-Hua Wang,
    • Sheng-Tao Yao,
    • Ye Lang,
    • Hai-Peng Li,
    • Craig S. Anderson,
    • Xun-Ming Ji,
    Endovascular treatment for cerebral venous thrombosis: a multicenter study in China, Military Medical Research, 12, 1, (2025).https://doi.org/10.1186/s40779-025-00605-3
    Crossref
    • Mariana B. Morais,
    • Diana Aguiar de Sousa,
    Pathophysiology and Management of Cerebral Venous Thrombosis, Hämostaseologie, (2025).https://doi.org/10.1055/a-2518-9103
    Crossref
    • Hong Khoi Vo,
    • Hong Thai Vu,
    Direct oral  anticoagulants versus warfarin in the treatment of cerebral venous thrombosis in bach mai hospitalThuốc chống đông đường uống trực tiếp và wafarin trong điều trị huyết khối tĩnh mạch não tại Bệnh viện Bạch Mai, Tạp chí thần kinh học Việt Nam, 44, (66-73), (2025).https://doi.org/10.62511/vjn.44.2025.052
    Crossref
    • Ying Liu,
    • Jinlong Zhao,
    • Jing Guo,
    • Yu Liu,
    • Chenlu Ma,
    • Yan Zhang,
    Low-Dose Dabigatran for Venous Sinus Thromboembolism Associated with Hereditary Dysfibrinogenemia: A Case Report, British Journal of Hospital Medicine, 86, 3, (1-10), (2025).https://doi.org/10.12968/hmed.2024.0426
    Crossref
    • Anabel Franco-Moreno,
    • Elena Madroñal-Cerezo,
    • Ana Martínez-Casa-Muñoz,
    • Judith Ortiz-Sánchez,
    • Cristina Lucía Ancos-Aracil,
    Direct Oral Anticoagulants for the Treatment of Unusual-Site Venous Thrombosis: An Update, Pharmaceutics, 17, 3, (342), (2025).https://doi.org/10.3390/pharmaceutics17030342
    Crossref
    • Kai Liu,
    • Mengmeng Zhang,
    • Jiawei Zhao,
    • Qinqin Dai,
    • Yuan Gao,
    • Shen Li,
    • Lu Zhao,
    • Yuming Xu,
    • Bo Song,
    Anticoagulant Therapy for Cerebral Venous Sinus Thrombosis: A Propensity Score Matching Study and Inverse Probability Weighting, Neurocritical Care, (2025).https://doi.org/10.1007/s12028-025-02225-0
    Crossref
    • Amber Afzal,
    • Frank Garrett Conyers,
    • Steven Sauk,
    • Jordan K. Schaefer,
    Venous Thromboembolism in Unusual Locations, Medical Clinics of North America, (2025).https://doi.org/10.1016/j.mcna.2025.01.007
    Crossref
  11. See more

View Options

View options

PDF and All Supplements

Download PDF and All Supplements

PDF/EPUB

View PDF/EPUB
Login options

Check if you have access through your login credentials or your institution to get full access on this article.

Personal login Institutional Login
Save for later Item saved, go to cart
Purchase Options

Purchase this article to access the full text.

Purchase access to this journal for 24 hours

Restore your content access

Enter your email address to restore your content access:

Note: This functionality works only for purchases done as a guest. If you already have an account, log in to access the content to which you are entitled.

Figures

Tables

Media

Share

Share

Share article link

Share

View full text|Download PDF

Comment Response