Treatment Outcomes of Direct Oral Anticoagulants in Cerebral Venous Thrombosis: A Prospective Observational Study in Vietnam
Conditions: Cerebral Venous Thrombosis
Sponsor: Hieu Trung Dinh

Study protocol: Treatment Outcomes of DOACs in CVT: A Prospective Study in Vietnam 
 
 
 
 
 
 
 
 
 
Treatment Outcomes of Direct Oral Anticoagulants in 
Cerebral Venous Thrombosis: A Prospective 
Observational Study in Vietnam 
 
 
 
 
 
Authors:  
Dinh Trung Hieu1,2, Nguyen Thanh Binh1, Mai Duy Ton1,2,3  
1. Hanoi Medical University, Hanoi, Vietnam 
2. Stroke Center, Bach Mai Hospital, Hanoi, Vietnam 
3. Faculty of Stroke and Cerebrovascular Disease, University of Medicine & 
Pharmacy, Vietnam National University, Hanoi, Vietnam 

Study protocol: Treatment Outcomes of DOACs in CVT: A Prospective Study in Vietnam 
 
 
TREATMENT OUTCOMES OF DOACs IN PATIENTS WITH CEREBRAL 
VENOUS THROMBOSIS: A PROSPECTIVE OBSERVATIONAL STUDY IN 
VIETNAM 
 
Short title 
Treatment Outcomes of DOACs in CVT 
Version 
1.0 
Date 
Update: 05/21/2025 
Project leader 
Dr. Dinh Trung Hieu 
Hanoi Medical University, Bach Mai Hospital 
Email: dr.dinhhieu1092@gmail.com 
Sponsor 
Self-funded 
Subsidising party 
None (self-funded) 
 
 
 

Study protocol: Treatment Outcomes of DOACs in CVT: A Prospective Study in Vietnam 
 
 
PROTOCOL SIGNATURE SHEET 
Name 
Signature 
Date 
Head of Deparment: 
Prof.dr. Mai Duy Ton 
 
 
Principal Investigator: 
Dr. Dinh Trung Hieu 
 
 
 
 
 

Study protocol: Treatment Outcomes of DOACs in CVT: A Prospective Study in Vietnam 
 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION AND RATIONALE .................................................... 3 
2. 
OBJECTIVE ......................................................................................... 4 
3. 
STUDY DESIGN .................................................................................. 6 
4. 
ELIGIBILITY CRITERIA ....................................................................... 7 
4.1. Population....................................................................................... 7 
4.2. Inclusion criteria .............................................................................. 7 
4.3. Exclusion criteria ............................................................................ 7 
5. 
METHODS ........................................................................................... 9 
5.1. Study endpoint ................................................................................ 9 
5.1.1. Primary study endpoint ............................................................. 9 
5.1.2. Secondary study endpoint ........................................................ 9 
5.2. Study procedures.......................................................................... 10 
5.3. Sample size .................................................................................. 11 
6. 
STATISTICAL ANALYSES ................................................................. 11 
7. 
ETHICAL CONSIDERATIONS ........................................................... 12 
8. 
LIMITATIONS ..................................................................................... 13 
9. 
Funding and Conflicts of Interest ....................................................... 14 
10. 
Administrative Aspects, Monitoring, and Publication ........................ 14 
10.1. 
Study Administration .................................................................. 14 
10.2. 
Data Management and Monitoring ............................................. 14 
10.3. 
Confidentiality ............................................................................ 15 
10.4. 
Protocol Amendments ................................................................ 15 
10.5. 
Publication Policy ...................................................................... 15 
 
 
 

Study protocol: Treatment Outcomes of DOACs in CVT: A Prospective Study in Vietnam 
 
 
LIST OF ABBREVIATIONS 
 
CVT 
Cerebral venous thrombosis 
 
DOACs 
Direct oral anticoagulants 
 
VKA 
Vitamin K antagonists 
 
RCT 
Randomized controlled trial 
 
NIHSS 
National Institutes of Health Stroke Scale 
 
mRS 
Modified Rankin Scale 
 
MRV 
Magnetic resonance venography 
 
CTV 
Computed tomography venography 
 
 
DSA 
Digital Subtraction Angiography 
 
ICH 
Intracranial hemorrhage 
 
ISTH 
International Society on Thrombosis and Haemostasis 
 

Study protocol: Treatment Outcomes of DOACs in CVT: A Prospective Study in Vietnam 
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SUMMARY 
Rationale: Cerebral venous thrombosis (CVT) is a rare condition. Once the diagnosis is 
established, current guidelines consistently recommend the early initiation of 
anticoagulation therapy with heparin, even in the presence of intracerebral hemorrhage. 
Upon clinical and radiological stabilization, treatment is typically transitioned to oral 
anticoagulants, including either vitamin K antagonists (VKA) or direct oral anticoagulants 
(DOACs). Since 2019, emerging evidence from randomized controlled trials such as 
RESPECT-CVT, CHOICE-CVT, and SECRET, along with large-scale international 
observational studies including ACTION-CVT and DOAC-CVT has demonstrated that 
DOACs can be safely used in the treatment of CVT. However, due to the rarity of the 
condition, most existing studies are limited by small sample sizes. Therefore, there is a 
growing need for additional studies across diverse geographic regions to expand the 
global evidence base on DOACs use in CVT. Such data will help enable more accurate 
assessment and analysis of treatment outcomes in patients with CVT receiving DOACs 
therapy. 
Objective: To evaluate treatment outcomes of DOAC therapy in CVT patients. 
Study Design: A prospective cohort study at Bach Mai Hospital, Vietnam, enrolling a 
minimum of 69 patients with CVT treated with DOACs. 
Study Population: Adult patients (≥18 years old) with radiologically confirmed CVT, 
treated with therapeutic-dose heparin in the acute phase and subsequently with a direct 
oral anticoagulant. All will be recruited from Bach Mai Hospital, the national referral center 
for CVT in northern Vietnam. 
Primary study endpoint: the primary endpoint is a composite of the number of patients 
who experience either major bleeding, as defined by the International Society on 
Thrombosis and Haemostasis (ISTH), or a venous thromboembolic event (VTE) - 
including recurrent CVT, deep vein thrombosis of any limb, pulmonary embolism, or 
splanchnic vein thrombosis — within up to 6 months of follow-up. 
 

Study protocol: Treatment Outcomes of DOACs in CVT: A Prospective Study in Vietnam 
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The secondary endpoint: 
• 
Mortality Rate: all death from any cause during the 6-month follow-up. 
• 
Functional outcome: proportion of patients with mRS 0–1 at 3 and 6 months. 
• 
Number of participants with major bleeding events 
• 
Number of participants with clinically relevant non-major bleeding (CRNMB) 
events 
• 
Number of participants with symptomatic recurrent venous thromboembolism 
(VTE) 
• 
Number of participants who discontinued anticoagulant therapy early 
• 
Number of participants with arterial thrombotic events 
• 
Number of participants with arterial thrombotic events 
• 
Serial D-dimer measurements after CVT 
• 
Venous recanalization 
• 
Frequency of chronic headache after CVT 
Nature and Extent of Risks, Burdens, and Benefits: This study is non-interventional in 
nature and does not introduce any additional procedures, risks, or burdens for 
participants. All information utilized will be obtained exclusively from standard clinical care 
and follow-up, without altering the course of treatment. No experimental interventions will 
be administered, and participation does not affect patients’ access to care or outcomes. 
ClinicalTrials.gov Identifier: 
 
 

Study protocol: Treatment Outcomes of DOACs in CVT: A Prospective Study in Vietnam 
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1. INTRODUCTION AND RATIONALE 
CVT accounts for only 0.5-1% of all diagnosed and treated stroke cases worldwide1. 
Previous studies have demonstrated that patients with CVT typically exhibit distinct 
clinical characteristics compared to those with other types of stroke. Notably, 
disproportionately affects younger individuals, with the majority of cases occurring in 
patients under 50 years of age and approximately two-thirds involving women2. Clinically, 
CVT often presents with symptoms associated with elevated intracranial pressure or focal 
brain parenchymal lesions, which may or may not be associated with mass effect3. 
Current international guidelines uniformly recommend initiating treatment with low-
molecular-weight heparin (LMWH) or unfractionated heparin during the acute phase. 
Once the clinical status and imaging findings have stabilized, oral anticoagulation is 
advised for a duration of 3-12 months, depending on the patient’s individual risk profile. 
In recent years, increasing attention has been directed toward the safety and efficacy of 
DOACs in the management of CVT. The first randomized controlled trial (RCT) evaluating 
DOAC use in CVT was the RESPECT-CVT trial4, published in 2019, which assessed 
dabigatran. This was followed by CHOICE-CVT5, was conducted in China. Both studies 
compared dabigatran with vitamin K antagonists (VKAs) and found no significant 
differences in safety and efficacy between the two groups. In 2023, the SECRET trial - an 
RCT comparing rivaroxaban with VKA - reported comparable outcomes6. However, due 
to the rarity of CVT, all of these RCTs were limited by relatively small sample sizes, 
underscoring the inherent difficulty of conducting large-scale RCTs for rare conditions.  
To complement these findings, large multicenter observational studies have been 
undertaken. Notably, the ACTION-CVT and DOAC-CVT studies have provided real-world 
evidence supporting the use of DOACs, demonstrating comparable safety and 
effectiveness to VKAs7,8. DOACs also offer several practical advantages, including fixed 
dosing, fewer drug–food interactions, and no requirement for routine INR monitoring. 
Nevertheless, even these observational studies have not enrolled patient numbers in the 
thousands, thereby limiting the statistical power for robust subgroup analyses. 

Study protocol: Treatment Outcomes of DOACs in CVT: A Prospective Study in Vietnam 
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Recent international guidelines now permit the use of either VKAs or DOACs in the 
treatment of CVT, acknowledging the growing body of evidence indicating similar safety 
and efficacy profiles9–11. Research in this area remains ongoing worldwide. 
In Vietnam, research on CVT treatment outcomes - particularly regarding the use of 
DOACs - is still limited. Moreover, due to the rarity of the condition and the complexity of 
evaluating multiple risk factors, patients with CVT are typically referred to major stroke 
centers for specialized management. Consequently, patient cohorts from such tertiary 
centers may provide insights that are representative of the national CVT population, 
rather than being confined to local or institutional patterns. 
The primary objective of the present study, Treatment Outcomes of DOACs in CVT, is to 
evaluate the real-world safety and efficacy of DOACs in the management of CVT in 
Vietnam. The secondary objective is to assess clinical outcomes and identify factors 
associated with treatment response during follow-up. 
2. OBJECTIVE 
Primary Objective 
To evaluate the effectiveness and safety of DOACs in patients with CVT over a 6-month 
follow-up period, using the composite outcome of major bleeding events or recurrent 
venous thromboembolism. 
Secondary Objectives 
Patients with CVT treated with DOACs will be assessed at 3 and 6 months to determine 
the following clinical outcomes: 
• Mortality Rate 
• Functional outcome 
• Number of participants with major bleeding events 
• Number of participants with clinically relevant non-major bleeding (CRNMB) 
events 
• Number of participants with symptomatic recurrent venous thromboembolism 
(VTE) 

Study protocol: Treatment Outcomes of DOACs in CVT: A Prospective Study in Vietnam 
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• Venous recanalization 
• Number of participants who discontinued anticoagulant therapy early 
• Number of participants with arterial thrombotic events 
• Frequency of participants with chronic headache after CVT 
• Health-related quality of life (EQ-5D-5L utility index score) 
• Serial D-dimer measurements after CVT 
 

Study protocol: Treatment Outcomes of DOACs in CVT: A Prospective Study in Vietnam 
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3.  STUDY DESIGN 
Treatment Outcomes of DOACs in CVT is a prospective, single-center observational 
study. The study involves the collection of treatment data during both the acute 
hospitalization phase and subsequent outpatient follow-up. It was conducted at Bach Mai 
Hospital, a central and tertiary referral center for the management of cerebral venous 
thrombosis (CVT) in Vietnam. 
A schematic diagram of the study design and follow-up is provided below 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion 
Baseline information 
3-month follow-up 
• Bleeding events or thrombotic 
• mRS 
• D-dimer 
• EQ-5D-5L 
6-month follow-up 
• Bleeding events or thrombotic 
• mRS 
• D-dimer 
• EQ-5D-5L 
• Imaging 

Study protocol: Treatment Outcomes of DOACs in CVT: A Prospective Study in Vietnam 
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4. ELIGIBILITY CRITERIA 
4.1. 
Population 
All consecutive adult patients diagnosed with CVT at Bach Mai Hospital were 
considered eligible for inclusion. Patients could be enrolled during initial hospitalization 
or through the outpatient stroke clinic. Both newly diagnosed cases and those referred 
from other facilities for further management were included. 
4.2. 
Inclusion criteria 
• Signed informed consent (ICF) to participate in the study 
• Age ≥ 18 years 
• Confirmed diagnosis of cerebral venous thrombosis (CVT) based on clinical 
presentation and neuroimaging, including one or more of the following: 
 
MRI and MRV, AND/OR 
 
CT and CTV, AND/OR 
 
MRI or CT combined with DSA 
• Initiation of DOACs within 5 to 15 days after starting treatment with heparin 
4.3. 
Exclusion criteria 
• CVT accompanied by antiphospholipid syndrome with all three positive laboratory 
criteria: lupus anticoagulant, anticardiolipin antibodies, and anti–β2-glycoprotein 
antibodies 
• CVT in pregnant patients requiring continuous anticoagulation throughout 
pregnancy 
• CVT with coexisting bleeding disorders, including immune thrombocytopenia with 
platelet count <100,000/mL, hemophilia A or B, von Willebrand disease, or a 
history of prolonged bleeding after surgery or invasive procedures 
• CVT in patients with mechanical heart valves, atrial fibrillation, and moderate to 
severe mitral stenosis 
• CVT in patients with a glomerular filtration rate (GFR) <15 mL/min 
• CVT with severe hepatic impairment 

Study protocol: Treatment Outcomes of DOACs in CVT: A Prospective Study in Vietnam 
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• Patients already receiving anticoagulation therapy for another underlying condition 
at the time of CVT diagnosis 
 
 

Study protocol: Treatment Outcomes of DOACs in CVT: A Prospective Study in Vietnam 
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5. METHODS 
5.1. 
Study endpoint 
5.1.1. Primary study endpoint 
The primary endpoint of the study is a composite outcome assessed over a 6-month 
follow-up period, comprising: (1) the occurrence of VTE, including recurrent CVT, deep 
vein thrombosis of any limb, pulmonary embolism, or thrombosis involving the 
splanchnic, jugular, caval, renal, or catheter-related veins; and (2) major bleeding 
events, defined according to the criteria established by the International Society on 
Thrombosis and Haemostasis (ISTH) (see Appendix B). 
5.1.2. Secondary study endpoint 
 
Assessed at 3 and 6 months (± 1 month): 
• Functional outcome: defined as a score of 0–1 on the Modified Rankin Scale 
(mRS). The mRS ranges from 0 (no symptoms) to 6 (death). Lower scores reflect 
better functional recovery. 
• Number of participants with major bleeding events: defined according to the criteria 
established by the International Society on Thrombosis and Haemostasis (ISTH)12 
(see Appendix B) 
• Number of participants with clinically relevant non-major bleeding (CRNMB) 
events: defined according to the criteria established by the International Society 
on Thrombosis and Haemostasis (ISTH)13 (see Appendix B) 
• Number of participants with symptomatic recurrent VTE 
• Health-related quality of life, measured by the EQ-5D-5L instrument and the 
Vietnamese population value set validated by Mai et al14.  
• Serial D-dimer measurements after CVT: plasma D-dimer levels will be measured 
at 3 and 6 months using a standardized quantitative assay. Values will be reported 
in ng/mL and interpreted in the context of post-CVT coagulation activity 
 
Assessed at 6 months (± 1 month): 

Study protocol: Treatment Outcomes of DOACs in CVT: A Prospective Study in Vietnam 
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• Mortality Rate 
• Number of participants who discontinued anticoagulant therapy early 
• Number of participants with arterial thrombotic events 
• Venous recanalization 
• Frequency of chronic headache following CVT 
5.2. 
Study procedures 
Baseline clinical and radiological data, including patient demographics, risk factors, 
imaging findings, anticoagulant treatment details, and in-hospital events during the acute 
phase of CVT, will be collected for all enrolled patients. 
Participants will be followed up at 3 and 6 months after diagnosis. Data collected at these 
time points will include: 
• 
Type and duration of oral anticoagulant therapy 
• 
Clinical events, including recurrent thrombotic or bleeding events 
• 
Degree of disability will be assessed using mRS 
• 
Venous recanalization will be assessed at 6 months using brain MRI with 
venography or CT venography. Recanalization will be categorized as complete, 
partial, or none, based on the classification proposed by Aguiar de Sousa et al15 
• Health-related quality of life, evaluated using the EQ-5D-5L instrument. This tool 
evaluates five domains (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression), each with five levels of severity. A utility index score will be 
calculated using the Vietnamese EQ-5D-5L value set, ranging from −0.511 to 
1.000, where:1.000 indicates perfect health, 0.000 corresponds to death, scores 
below 0 indicate health states considered worse than death by the general 
Vietnamese population. 
• 
Presence of chronic headache, defined as a headache occurring on ≥15 days per 
month and persisting for more than 3 months following the acute CVT event, 
consistent with the International Classification of Headache Disorders, 3rd edition 

Study protocol: Treatment Outcomes of DOACs in CVT: A Prospective Study in Vietnam 
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(ICHD-3)16. Headache-related disability, assessed using the Headache Impact 
Test (HIT-6)17 
All data will be collected as part of routine clinical care during outpatient visits or structured 
telephone interviews and recorded using standardized case report forms. 
5.3. 
Sample size 
Due to the rarity of the disease and the single-center design of the Treatment Outcomes 
of DOACs in CVT study, a minimum of 69 patients are expected to be enrolled over a 2-
year period starting in June 2025. Patient recruitment is anticipated to be completed by 
June 2027, with final 6-month follow-up assessments expected to conclude by December 
2027. 
6. STATISTICAL ANALYSES 
All statistical analyses will be conducted using R software (version 4.4.1). Statistical 
significance will be set at a two-sided p-value < 0.05. 
Descriptive statistics will be used to summarize baseline characteristics. Continuous 
variables will be reported as means ± standard deviations (SD) or medians with 
interquartile ranges (IQR), depending on distribution. Categorical variables will be 
expressed as counts and percentages. 
The primary endpoint: a composite of major bleeding (per ISTH criteria) or symptomatic 
recurrent venous thromboembolism (VTE), including cerebral venous thrombosis, deep 
vein thrombosis, pulmonary embolism, or splanchnic vein thrombosis—will be analyzed 
as a time-to-event outcome. Kaplan–Meier survival curves will be constructed, and group 
comparisons will be performed using the log-rank test. Cumulative event rates at 6 
months will be reported with 95% confidence intervals. 
For secondary endpoints, the following analyses will be conducted: 
• 
Functional outcome (mRS 0-1 vs 2-6 at 3 and 6 months) will be analyzed using 
logistic regression to identify predictors of favorable recovery. 

Study protocol: Treatment Outcomes of DOACs in CVT: A Prospective Study in Vietnam 
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• 
Venous recanalization status at 6 months will be described as complete, partial, or 
absent, based on follow-up imaging, and summarized as proportions. 
• 
Rates of major bleeding, any bleeding, symptomatic recurrent VTE, and arterial 
thrombotic events will be summarized descriptively and reported with 95% 
confidence intervals. 
• 
Health-related quality of life (EQ-5D-5L), chronic post-CVT headache (HIT-6), at 3 
and 6 months will be compared using paired t-tests or Wilcoxon signed-rank tests, 
as appropriate. 
• 
Changes in D-dimer levels from baseline to follow-up will be analyzed using paired 
tests and visualized longitudinally. 
Missing data will be handled using complete case analysis. If the missing rate exceeds 
10% for any variable, sensitivity analyses will be performed. 
7. ETHICAL CONSIDERATIONS 
This study is a doctoral research project conducted as part of the PhD training program 
at Hanoi Medical University. The study was officially approved by the university on March 
3, 2025, under Decision No. 580/QĐ-ĐHYHN. 
Ethical approval was granted by the Ethics Committee of Bach Mai Hospital on July 4, 
2025, under Decision No. 45/BM-HĐĐĐ. The study will be conducted in accordance with 
the principles of the Declaration of Helsinki (2013) and Good Clinical Practice (GCP) 
guidelines. The research will take place at Bach Mai Hospital, a national tertiary referral 
center for cerebrovascular diseases in Vietnam. 
All eligible participants will be required to provide written informed consent before 
enrollment. Patients will be informed of the study’s purpose, procedures, potential risks 
and benefits, their rights to confidentiality, and the option to withdraw from the study at 
any point without affecting their ongoing care. 
This is a prospective, observational study. All interventions and follow-up procedures are 
part of standard clinical management for patients with cerebral venous thrombosis (CVT). 

Study protocol: Treatment Outcomes of DOACs in CVT: A Prospective Study in Vietnam 
13 
 
No experimental drugs or procedures will be introduced. Treatment decisions—including 
the use of direct oral anticoagulants—are made entirely by the attending physicians 
based on current guidelines and clinical judgment. 
To protect privacy, personal data will be de-identified and stored on secure hospital 
servers with restricted access. Only aggregated, anonymized data will be used for 
publication or dissemination. 
Any protocol deviations or serious adverse events observed during the study will be 
documented and reported to the Institutional Review Board (IRB) in accordance with 
national and institutional regulations. 
8. LIMITATIONS 
This study has several limitations. First, it is a single-center investigation conducted at 
Bach Mai Hospital, a national tertiary referral center. While this may raise concerns 
regarding generalizability, the hospital receives the majority of CVT cases from a wide 
geographic area in northern Vietnam, including referrals from provincial and district-level 
hospitals. Therefore, the study population is expected to be broadly representative of the 
CVT patient population in real-world clinical practice within the region. 
Second, given the rarity of CVT and the fixed 2-year enrollment window, the sample size 
is expected to be limited. This may reduce the statistical power to perform robust 
subgroup analyses or develop complex multivariable models. However, the study is 
designed to maximize data completeness through close follow-up and adherence to 
protocol-defined procedures. 
Third, although the study currently includes both DOAC and VKA group, the planned 
analysis will primarily focus on the DOAC subgroup. This approach reflects the growing 
interest in the real-world effectiveness and safety of DOACs in CVT management. 
Including VKA patients in the recruitment phase may still provide useful contextual 
information for future comparative analyses. 

Study protocol: Treatment Outcomes of DOACs in CVT: A Prospective Study in Vietnam 
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Finally, some outcome data, such as follow-up imaging for venous recanalization or 
standardized cognitive assessments, may be unavailable for a small number of patients 
due to loss to follow-up or logistical constraints. Nonetheless, the study team is committed 
to minimizing missing data through proactive patient engagement and structured follow-
up planning. 
 
 
9. Funding and Conflicts of Interest 
This study is investigator-initiated and self-funded. All study-related activities, including 
patient recruitment, data collection, follow-up, and statistical analysis, are carried out 
using the resources of the research team at the Bach Mai Hospital. No external funding 
or sponsorship has been obtained from pharmaceutical companies, academic 
institutions, or governmental agencies. 
The investigators declare no conflicts of interest. There are no financial, institutional, or 
personal relationships that could be perceived to influence the design, conduct, 
interpretation, or publication of this study. 
10. Administrative Aspects, Monitoring, and Publication 
10.1. Study Administration 
The study is conducted under the supervision of Bach Mai Hospital. A designated 
principal investigator is responsible for overall coordination, compliance with the protocol, 
and ensuring data quality. Study procedures are implemented in accordance with the 
approved protocol, Good Clinical Practice (GCP), and local regulatory requirements. 
10.2. Data Management and Monitoring 
Study data will be collected and stored in a secure, password-protected electronic 
database. Data entry will be performed by trained personnel and subject to regular quality 

Study protocol: Treatment Outcomes of DOACs in CVT: A Prospective Study in Vietnam 
15 
 
control checks. The study team will periodically monitor data for completeness, 
consistency, and adherence to the study protocol. No formal external monitoring or 
auditing is planned, given the observational and non-interventional nature of the study. 
10.3. Confidentiality 
Patient confidentiality will be strictly maintained. All data will be de-identified and coded 
using unique study identifiers. Access to identifiable patient information will be restricted 
to authorized personnel only. 
10.4. Protocol Amendments 
Any significant changes to the study protocol will be documented, submitted for ethical 
approval, and communicated to all relevant parties, including the study registry if 
applicable. 
10.5. Publication Policy 
The results of the study will be disseminated through scientific publications and 
conference presentations. Authorship will follow the criteria established by the 
International Committee of Medical Journal Editors (ICMJE). The research team is 
committed to transparency and will ensure that study findings are made publicly 
accessible regardless of outcome. 
 

Study protocol: Treatment Outcomes of DOACs in CVT: A Prospective Study in Vietnam 
 
 
REFERENCES 
1. Bousser MG, Ferro JM. Cerebral venous thrombosis: an update. Lancet Neurol. 
2007;6(2):162-170. doi:10.1016/S1474-4422(07)70029-7 
2. Alet M, Ciardi C, Alemán A, et al. Cerebral venous thrombosis in Argentina: clinical 
presentation, predisposing factors, outcomes and  literature review. J Stroke 
Cerebrovasc 
Dis 
Off 
J 
Natl 
Stroke 
Assoc. 
2020;29(10):105145. 
doi:10.1016/j.jstrokecerebrovasdis.2020.105145 
3. Saposnik G, Barinagarrementeria F, Brown RD, et al. Diagnosis and Management of 
Cerebral Venous Thrombosis: A Statement for Healthcare Professionals From the 
American Heart Association/American Stroke Association. Stroke. 2011;42(4):1158-
1192. doi:10.1161/STR.0b013e31820a8364 
4. Ferro JM, Coutinho JM, Dentali F, et al. Safety and Efficacy of Dabigatran Etexilate vs 
Dose-Adjusted Warfarin in Patients With Cerebral Venous Thrombosis: A 
Randomized 
Clinical 
Trial. 
JAMA 
Neurol. 
2019;76(12):1457. 
doi:10.1001/jamaneurol.2019.2764 
5. Ma H, Gu Y, Bian T, et al. Dabigatran etexilate versus warfarin in cerebral venous 
thrombosis in Chinese patients (CHOICE-CVT): An open-label, randomized controlled 
trial. Int J Stroke. 2024;19(6):635-644. doi:10.1177/17474930241234749 
6. Field TS, Dizonno V, Almekhlafi MA, et al. Study of Rivaroxaban for Cerebral Venous 
Thrombosis: A Randomized Controlled Feasibility Trial Comparing Anticoagulation 
With Rivaroxaban to Standard-of-Care in Symptomatic Cerebral Venous Thrombosis. 
Stroke. 2023;54(11):2724-2736. doi:10.1161/STROKEAHA.123.044113 
7. Yaghi S, Shu L, Bakradze E, et al. Direct Oral Anticoagulants Versus Warfarin in the 
Treatment of Cerebral Venous Thrombosis (ACTION-CVT): A Multicenter 
International 
Study. 
Stroke. 
2022;53(3):728-738. 
doi:10.1161/STROKEAHA.121.037541 
8. Van De Munckhof A, Van Kammen MS, Tatlisumak T, et al. Direct oral anticoagulants 
versus vitamin K antagonists for cerebral venous thrombosis (DOAC-CVT): an 
international, prospective, observational cohort study. Lancet Neurol. 2025;24(3):199-
207. doi:10.1016/S1474-4422(24)00519-2 
9. Saposnik G, Bushnell C, Coutinho JM, et al. Diagnosis and Management of Cerebral 
Venous Thrombosis: A Scientific Statement From the American Heart Association. 
Stroke. 2024;55(3). doi:10.1161/STR.0000000000000456 
10. Ulivi L, Squitieri M, Cohen H, Cowley P, Werring DJ. Cerebral venous thrombosis: a 
practical guide. Pract Neurol. 2020;20(5):356-367. doi:10.1136/practneurol-2019-
002415 

Study protocol: Treatment Outcomes of DOACs in CVT: A Prospective Study in Vietnam 
 
 
11. Field TS, Lindsay MP, Wein T, et al. Canadian Stroke Best Practice 
Recommendations, 7th Edition: Cerebral Venous Thrombosis, 2024. Can J Neurol 
Sci. 2025;52(3):353-369. doi:10.1017/cjn.2024.269 
12. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of 
antihemostatic medicinal products in non‐surgical patients. J Thromb Haemost. 
2005;3(4):692-694. doi:10.1111/j.1538-7836.2005.01204.x 
13. Kaatz S, Ahmad D, Spyropoulos AC, Schulman S. Definition of clinically relevant non‐
major bleeding in studies of anticoagulants in atrial fibrillation and venous 
thromboembolic disease in non‐surgical patients: communication from the SSC of the 
ISTH. J Thromb Haemost. 2015;13(11):2119-2126. doi:10.1111/jth.13140 
14. Mai VQ, Sun S, Minh HV, et al. An EQ-5D-5L Value Set for Vietnam. Qual Life Res. 
2020;29(7):1923-1933. doi:10.1007/s11136-020-02469-7 
15. Aguiar De Sousa D, Lucas Neto L, Arauz A, et al. Early Recanalization in Patients 
With Cerebral Venous Thrombosis Treated With Anticoagulation. 
Stroke. 
2020;51(4):1174-1181. doi:10.1161/STROKEAHA.119.028532 
16. Society (IHS) HCC of the IH. The International Classification of Headache Disorders, 
3rd edition. Cephalalgia. 2018;38(1):1-211. doi:10.1177/0333102417738202 
17. Yang M, Rendas-Baum R, Varon SF, Kosinski M. Validation of the Headache Impact 
Test (HIT-6TM) across episodic and chronic migraine. Qual Life Res. 2011;20(7):1071-
1078. doi:10.1007/s11136-010-9836-0 
 
 
 

Study protocol: Treatment Outcomes of DOACs in CVT: A Prospective Study in Vietnam 
 
 
APPENDIX A. 
Standard Operating Procedure for the Scoring of Cerebral Venous Recanalization 
Objective 
Imaging Modalities Accepted 
• Magnetic resonance venography (MRV) 
• Computed tomography venography (CTV) 
• Digital subtraction angiography (DSA), if available 
Grade 
Definition 
0 
No recanalization: Persistent occlusion with no visible flow. 
1 
Partial recanalization: Incomplete restoration of venous flow. 
2 
Complete recanalization: Full restoration of flow with no residual 
occlusion. 
 
 

Study protocol: Treatment Outcomes of DOACs in CVT: A Prospective Study in Vietnam 
 
 
APPENDIX B. 
ISTH Definitions of Major and Clinically Relevant Non-Major Bleeding 
Major Bleeding 
Defined according to the International Society on Thrombosis and Haemostasis (ISTH) 
criteria12 as any of the following: 
• Fatal bleeding 
• Symptomatic bleeding in a critical area or organ (e.g., intracranial, intraspinal, 
intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, 
or retroperitoneal) 
• Bleeding causing a fall in hemoglobin of ≥2 g/dL 
• Bleeding leading to transfusion of ≥2 units of whole blood or red cells 
Clinically Relevant Non-Major Bleeding 
As per ISTH SSC definition13: Bleeding that does not meet the criteria for major bleeding 
AND is associated with one or more of the following: 
• Requires medical intervention by a healthcare professional 
• Leads to unscheduled contact with a physician (visit or telephone) 
• Results in temporary cessation of anticoagulation therapy 
• Causes discomfort or impairment of activities of daily living