Direct Oral Anticoagulants for the Treatment of Cerebral Venous Thrombosis: An International Phase IV Study
Conditions: Cerebral Venous Thrombosis
Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

DOAC-CVT Study Protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
DOAC-CVT  
Direct Oral Anticoagulants for the treatment of 
Cerebral Venous Thrombosis 
 
 
 
 
 
 
 
 
 
 
 
Authors: 
Mayte Sánchez van Kammen1, Anita van de Munckhof1, Jose M. Ferro2, Turgut Tatlisumak3, Jukka Putaala4, 
Jonathan M. Coutinho1 
 
1. 
Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands 
2. 
Hospital da Luz, University of Lisbon, Lisbon, Portugal  
3. 
Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy 
at University of Gothenburg and Department of Neurology, Sahlgrenska University Hospital, Gothenburg, 
Sweden 
4. 
Department of Neurology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland 

DOAC-CVT Study Protocol 
 
 
 
DIRECT ORAL ANTICOAGULANTS FOR THE TREATMENT OF CEREBRAL VENOUS 
THROMBOSIS: AN INTERNATIONAL PHASE IV STUDY  
 
Short title 
DOAC-CVT 
Version 
3.1 
Date 
Update: 13-08-2024 
Project leader 
 
Dr. Jonathan Coutinho 
Amsterdam UMC 
Email: j.coutinho@amsterdamumc.nl  
Principal investigator(s)  
See Appendix D 
Sponsor  
Amsterdam UMC 
Meibergdreef 9 
1105 AZ Amsterdam 
Subsidising party 
Trombosestichting Nederland 
Dobbeweg 1a 
2254 AG Voorschoten 

DOAC-CVT Study Protocol 
 
 
 
PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department: 
Prof.dr. D. van de Beek 
 
 
Principal Investigator: 
Dr. J. Coutinho 
 
 
 
 

DOAC-CVT Study Protocol 
 
 
 
TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE ................................................................................. 7 
2. 
OBJECTIVES .................................................................................................................... 9 
3. 
STUDY DESIGN ............................................................................................................. 10 
4. 
STUDY POPULATION .................................................................................................... 12 
4.1 
Population ................................................................................................................ 12 
4.2 
Inclusion criteria ....................................................................................................... 12 
4.3 
Exclusion criteria ...................................................................................................... 12 
4.4 
Sample size calculation ........................................................................................... 12 
5. 
METHODS ...................................................................................................................... 14 
5.1 
Study parameters/endpoints .................................................................................... 14 
5.1.1 
Primary study endpoint ..................................................................................... 14 
5.1.2 
Secondary study endpoints .............................................................................. 14 
5.2 
Study procedures ..................................................................................................... 15 
5.3 
Withdrawal of individual subjects ............................................................................. 15 
5.4 
Premature termination of the study .......................................................................... 15 
6. 
STATISTICAL ANALYSES ............................................................................................. 16 
6.1 
Primary study endpoint ............................................................................................ 16 
6.1.1 
Main analysis of primary endpoint .................................................................... 16 
6.1.2 
Sensitivity analyses for the primary endpoint ................................................... 17 
6.1.3 
Subgroup analysis of primary endpoint ............................................................ 18 
6.2 
Secondary study parameter(s) ................................................................................. 18 
7. 
ETHICAL CONSIDERATIONS ........................................................................................ 19 
7.1 
Regulation statement ............................................................................................... 19 
7.2 
Recruitment and consent ......................................................................................... 19 
7.3 
Benefits and risks assessment ................................................................................ 19 
8. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ............................. 20 
8.1 
Handling and storage of data and documents ......................................................... 20 
8.2 
Study Oversight ....................................................................................................... 20 
8.3 
Public disclosure and publication policy ................................................................... 22 

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LIST OF ABBREVIATIONS  
 
CVT 
Cerebral venous thrombosis 
VKA 
Vitamin K antagonists 
DOAC 
Direct oral anticoagulants 
VTE 
Venous thromboembolism 
NIHSS 
National Institutes of Health Stroke Scale 
MRV 
Magnetic resonance venography 
ICH 
Intracranial hemorrhage 
CNS 
Central nervous system 
mRS 
Modified Rankin Scale 
ISTH 
International Society on Thrombosis and Haemostasis 
IRB 
Institutional Review Board 
GDPR 
General Data Protection Regulation 
eGFR 
Estimated glomerular filtration rate 
 
 

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SUMMARY 
 
Rationale: Patients with cerebral venous thrombosis (CVT) are currently treated with 
anticoagulants during 3-12 months after diagnosis, to prevent worsening of the CVT and 
recurrent thrombosis, and to promote venous recanalization. Until recently, patients were 
generally treated with vitamin K antagonists (VKA). Direct oral anticoagulants (DOACs) are 
more practical in use than VKA and carry a lower risk of intracranial hemorrhage (ICH) in 
other conditions. One of the burning clinical questions is whether CVT patients can be safely 
treated with DOACs instead of VKA. In 2019, the first randomized trial on the safety and 
efficacy of DOACs in CVT was published (RESPECT-CVT). This exploratory study included 
120 patients and the results suggest that DOACs can be safely used to treat CVT. Following 
RESPECT-CVT, use of DOACs to treat CVT is expected to rise, but given the limited sample 
size and strict selection criteria of RESPECT-CVT, additional data regarding the efficacy and 
safety of DOACs in CVT are required, especially from routine clinical care. 
Objective: To assess the safety and efficacy of DOACs for the treatment of CVT in a real-
world setting. 
Study design: DOAC-CVT will be an international, prospective, comparative cohort study. 
We aim to recruit 1300 patients and anticipating a 3:2 ratio in DOAC:VKA use, we expect 
that in total 780 patients treated with a DOAC will be included. 
Study population: Patients are eligible if they are >18 years old, have a radiologically 
confirmed CVT, and have started oral anticoagulant treatment (DOAC or VKA) within 30 
days of CVT diagnosis. 
Primary study endpoint: The primary endpoint is a composite of major bleeding (according 
to the criteria of the International Society on Thrombosis and Haemostasis) AND 
symptomatic recurrent venous thrombosis after 6 months of follow-up.  
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: This is an observational study which poses no risk or burden to the 
participant. Only data that are collected as part of routine clinical care will be used. 
ClinicalTrials.gov Identifier: NCT04660747 
 
 
 
 
 
 
 

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1. INTRODUCTION AND RATIONALE 
Cerebral venous thrombosis (CVT) is an uncommon thrombotic disorder that mainly affects 
young adults and children (Figure 1).1 CVT often leads to severe neurological deficits, 
epileptic seizures, and decreased consciousness, and has a mortality rate of 5-15%.2,3 A 
unique aspect of CVT is that the increased cerebral venous pressure leads to an 
intracerebral hemorrhage (ICH) in about 40% of patients.2 Despite this high risk of major 
bleeding, anticoagulation is widely considered the main treatment for CVT, based on 
evidence from two small randomized trials.4 Current guidelines recommend initial treatment 
with (low-molecular weight) heparin for 1-2 weeks, followed by vitamin K antagonists (VKA) 
for 3-12 months.5,6 
 
Figure 1. T1-weighted MRI (A) and MR-venography (B) of a patient with superior sagittal sinus 
thrombosis.  
 
 
 
 
 
 
 
 
 
 
 
A: Mid-sagittal T1 weighted MRI showing hyperintensity in the superior sagittal sinus, indicating fresh thrombus 
within the venous sinus (white arrows). 
B: Sagittal MR-venogram of the same patient. There is absence of flow within the superior sagittal sinus, 
confirming there is a thrombosis in this vein (white arrows). There is normal opacification of the lateral sinus 
(black arrow). 
 
One of the current burning clinical questions is whether CVT patients can be safely and 
effectively treated with direct oral anticoagulants (DOACs) instead of VKA. Apart from the 
practical advantages (stable dosing, no monitoring required), the substantially lower risk of 
ICH with DOACs compared to VKA in both venous thromboembolism and atrial fibrillation 
has sparked worldwide interest among neurologists.7,8  
In 2019, the results of the first randomized trial on DOACs in CVT (RESPECT-CVT) were 
published.9 The study was not powered for either superiority or non-inferiority, since it was 
clear from the start that such a large sample size would not be achievable in a disease as 
A 
B 

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rare as CVT. Nevertheless, the data of RESPECT-CVT indicate that dabigatran has a similar 
efficacy and safety as INR-adjusted warfarin for the treatment of CVT. A few small10,11 and 
non-peer-reviewed12 cohort studies have been published indicating results in the same 
direction.13 Following the results of RESPECT-CVT, as well as the recent randomized 
SECRET-CVT trial and the retrospective ACTION-CVT study,14,15 the use of DOACs to treat 
CVT is expected to rise. However, given the limited sample size and the strict inclusion and 
exclusion criteria of the randomized trials, additional data regarding the safety and efficacy of 
DOACs in CVT are much needed, especially data from routine clinical care.  
 
DOAC-CVT will also provide more data on outcomes after CVT. While the mortality of CVT 
has decreased over the years,3 several small-scale studies indicate that many CVT survivors 
suffer from chronic and debilitating symptoms, such as headache, fatigue, and concentration 
deficits.16,17 The frequency and consistency of chronic symptoms in these studies suggest the 
existence of a “post-CVT syndrome”, similar to the post-thrombotic syndrome seen in 
patients after a leg-vein thrombosis. While these studies clearly suggest that post-CVT 
syndrome commonly occurs, their small size limits the validity and generalizability of the 
data. The overall thrombotic recurrence rate after CVT is estimated at 5-10%,2,18 which is 
lower than observed in other types of venous thromboembolism (VTE), but sufficiently 
powered, prospective, international studies are lacking. It is also unknown what the 
recurrence rate is according to the underlying risk profile, i.e. transient risk factors, persistent 
risk factors, and unprovoked thrombosis. More data about the post-CVT syndrome and long-
term recurrence rate of VTE are urgently required, both for patient education and to guide 
future studies on how to mitigate this problem.  
 
The main aim of the DOAC-CVT study (Direct oral anticoagulants for the treatment of 
cerebral venous thrombosis: an international phase IV study) will be to validate the efficacy 
and safety data of RESPECT-CVT in a real-world setting. Secondary aims are to investigate 
the frequency and burden of chronic post-CVT symptoms and the long-term thrombotic 
recurrence rate after CVT. 
 
 
 

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2. OBJECTIVES 
 
Primary Objective 
To assess the safety and efficacy of DOACs vs. VKAs in patients with CVT, in terms of the 6-
month risk of symptomatic recurrent VTE or major bleeding. 
 
Secondary Objectives 
In patients with CVT treated with DOACs vs. VKAs, to assess the 3, 6- and 12-month*: 
- 
All-cause mortality  
- 
Symptomatic recurrent VTE rate 
- 
Major bleeding rate  
- 
Clinically relevant non-major bleeding rate 
- 
Arterial thrombotic event rate 
- 
Modified Rankin Scale score 
- 
Oral anticoagulant cross-over rate with reasons for cross-over 
- 
Cerebral venous recanalization rate at 6 months** 
- 
Frequency of chronic post-CVT symptoms at 12 months 
- 
Thrombotic recurrence rate at 24 months 
* 12-month follow-up: if performed as part of routine care 
** Only in centers that perform 6-month follow-up imaging as part of routine clinical care 
 
 
 
 

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3. STUDY DESIGN 
 
DOAC-CVT is an international, prospective, phase IV, comparative observational cohort 
study. The study will use data that are collected as part of routine clinical care. It will be 
carried out during the course of 5 years in more than 60 hospitals worldwide with 
expertise in the treatment of CVT. Since this is an observational study, the choice of 
anticoagulant type and duration of treatment are left at the discretion of the treating 
physicians and patients. No treatment, intervention, or examinations are imposed on 
patients in the context of this study.  
 
A blinded adjudication committee will evaluate the occurrence of the following endpoints: 
symptomatic recurrent VTE, major bleeding, clinically relevant non-major bleeding, 
arterial thrombotic events, and death (classified as cardiovascular, non-cardiovascular, or 
undetermined cause). Adjudication will be based on a standardized report form describing 
relevant clinical information and diagnostic test results, including slices of relevant 
imaging and local imaging reports. Using the available data, the adjudication committee 
will decide whether the registered event can be classified as a primary outcome 
(thrombotic or bleeding event). The adjudication committee will be blinded to the type of 
anticoagulant given (DOAC vs VKA). 
 

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Figure 2. Flowchart of baseline and follow-up time points and routine assessments at each time point* 
 
*If part of routine care. Follow-up visits may be by phone or video 

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4. STUDY POPULATION 
4.1 Population 
Consecutive patients with CVT treated at the participating centres. Both patients who are 
admitted to the hospital and patients who are treated via outpatient clinic are eligible. A 
recruitment log will be kept by participating centers, which will also list non-included CVT 
patients with reasons of exclusion.  
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
 
- 
Written informed consent for the use of observational data 
- 
Age >18 years at the time of CVT diagnosis 
- 
Radiologically confirmed CVT diagnosis (CT-venography, MRI or catheter 
angiography) 
- 
Oral anticoagulant treatment (DOAC or VKA) started within 30 days of CVT 
diagnosis (patient may initially be treated with heparin) 
- 
Inclusion in the study within 90 days of CVT diagnosis 
 
4.3 Exclusion criteria 
As this is a phase IV study, the patient population should reflect routine clinical practice as 
much as possible. As such, the only exclusion criteria will be prevalent users and absolute 
contra-indications for the use of DOACs, i.e.:  
 
• 
Anticoagulant treatment at the time of CVT diagnosis 
• 
Pregnancy or lactation (post-partum women are eligible if they do not give breast-
feeding) 
• 
Mechanical heart valve 
• 
Severe renal insufficiency (defined as an eGFR <15 ml/min) 
• 
Severe liver disease resulting in clinically relevant coagulopathy  
 
4.4 Sample size calculation 
DOAC-CVT is designed as a pragmatic exploratory phase IV study. Initially, DOAC-CVT 
was designed to recruit 500 patients in a three-year study period (until 15 January 2024).  
This convenience sample size was chosen because recruiting more patients was 
considered unfeasible due to the rarity of the disease. Now that international collaboration 

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and recruitment speed has exceeded expectations, recruitment in the DOAC-CVT study 
will continue for two additional years (until January 2026). As of January 2024, 635 
patients have been recruited in the DOAC-CVT study. With an inclusion rate of 
approximately 30 patients per month, we expect to be able to recruit 1300 patients with 
CVT by the end of the study period in January 2026.   
 
 

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5. METHODS 
5.1 Study parameters/endpoints 
5.1.1 
Primary study endpoint 
The primary endpoint is the composite of symptomatic recurrent VTE (i.e. recurrent 
CVT, DVT of any limb, pulmonary embolism, splanchnic vein, jugular, caval, renal, 
or catheter-related thrombosis) AND major bleeding (according to the criteria of the 
International Society on Thrombosis and Haemostasis [ISTH]19; see Appendix B) 
after 6 months of follow-up.  
 
5.1.2 
Secondary study endpoints  
Assessed at 3, 6 and 12 months*: 
- 
All-cause mortality  
- 
Symptomatic recurrent VTE rate 
- 
Major bleeding rate19 (see Appendix B) 
- 
Clinically relevant non-major bleeding rate20 (see Appendix B) 
- 
Arterial thrombotic event rate 
- 
Modified Rankin Scale score 
- 
Oral anticoagulant crossover rate with reasons for crossover 
 
Assessed at 6 months**: 
- 
Cerebral venous recanalization rate – only if assessed as part of routine 
care  
 
            Assessed at 12 months*: 
- 
Frequency of chronic post-CVT symptoms 
 
 
            Assessed at 24 months: 
- 
Symptomatic recurrent VTE rate 
 
* ± 1 month; 12-month follow-up only if performed as part of routine care 
** ± 2 months; cerebral venous recanalization will be scored according to the 
previously published Aguiar de Sousa classification21 (see Appendix A) 
 

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5.2 Study procedures 
Baseline clinical and radiological data, treatment details, and events during primary 
admission will be collected for all patients. Participants will be followed-up at 3, 6, 
12, and 24 months after diagnosis. This study will only analyse data that are 
collected as part of routine clinical care. Data collected during the 3-, 6-, and 12-
month follow-up visit include anticoagulant treatment details, imaging, clinical 
events, and functional outcome. Since not all hospitals perform a head MR with MR-
venography or CT-venography at the 6-month follow-up visit as part of routine care, 
data on venous recanalization will be missing for some participating centers. Quality 
of life (EQ-5D-5L), residual symptoms, psychological distress (Hospital Anxiety and 
Depression Scale), and vocational outcomes (Work Ability Score) will be collected 
for all patients at the 12-month follow-up moment, as part of routine care, in 
accordance with Dutch and international stroke guidelines.22-24 In case a patient 
reports headache, fatigue, or cognitive impairment, standardized questionnaires 
(Headache Impact Test-6, Fatigue Assessment Scale, and Checklist for Cognitive 
and Emotional Consequence of Stroke [CLCE-24; questions 1 to 13], respectively) 
will be collected to further evaluate the extent of these residual symptoms. The long-
term VTE recurrence rate will be collected at 24 months after CVT diagnosis.  
 
5.3 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without 
any consequences.  
 
5.4    Premature termination of the study 
The study will be prematurely terminated if the Steering Committee decides this 
observational study is no longer clinically relevant, e.g. because new insights have 
rendered the research question irrelevant. In case of premature study termination, 
the results of the study thus far will be published as an exploratory report.  

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6. STATISTICAL ANALYSES 
Baseline characteristics will be presented for patients who are initially started on a DOAC 
and those who are initially started on VKA. Categorical data will be presented as counts 
and proportions, continuous data as means and standard deviations or medians and 
(interquartile) ranges, as appropriate. Missing data on confounders will be imputed using 
multiple imputation. 
 
6.1 Primary study endpoint 
6.1.1 
Main analysis of primary endpoint 
Comparisons will be made according to the intention-to-treat principle (i.e. according 
to the first oral anticoagulant that was started). Based on the results of the RESPECT 
CVT trial,9 we expect an approximate 1.7% event rate for the primary outcome in the 
DOAC group and a 3.3% event rate in the VKA group, i.e. around 12 events in the 
total sample. 
 
We will use propensity score inverse probability treatment weighting to calculate an 
adjusted odds ratio for the primary outcome. Based on the direct acyclic graph 
(Figure 3), the following confounders will be used to compute the propensity score: 
• 
Age at time of CVT diagnosis 
• 
ICH at CVT diagnosis, or after diagnosis but before start of oral anticoagulant 
treatment 
• 
Glasgow Coma Scale at CVT diagnosis  
• 
CNS infection concurrent with the index CVT 
• 
Known antiphospholipid syndrome, or presence of antiphospholipid antibodies at 
start of oral anticoagulant treatment 
• 
Cancer (defined as currently under treatment or diagnosed within 6 months prior 
to start of oral anticoagulant treatment)  
• 
Previous VTE 
• 
Previous major bleeding prior to the index CVT (according to ISTH criteria) 
• 
Baseline renal function 
• 
Concomitant antiplatelet use at start of oral anticoagulant treatment 
• 
Country of inclusion’s income group as classified by The World Bank. 

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We will analyze the balance of confounders among both treatment groups after 
propensity score inverse probability-weighting. A last observation carried forward 
approach will be used if the 6- or 12-month follow-up data are missing. 
 
Figure 3. Directed Acyclic Graph depicting factors influencing anticoagulant treatment choice 
and risk of recurrent venous thrombotic event or major bleeding 
 
6.1.2 
Sensitivity analyses for the primary endpoint 
In addition to the main analysis of the primary endpoint, we will perform four 
sensitivity analyses for the primary endpoint. Firstly, we will perform a survival 

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analysis of the primary endpoint using the inverse probability weighting from the main 
analysis. Patients will be censored at the time of anticoagulant-switch or at the last 
follow-up moment (after 3, 6, or 12 months). Secondly, we will provide unadjusted 
analyses. Thirdly, we will repeat the analysis conducting a worst-case scenario 
approach i.e. using the assumption that all patients with missing outcome data would 
have suffered a primary endpoint event. Lastly, we will perform a descriptive on-
treatment analysis. 
6.1.3 
Subgroup analysis of primary endpoint 
In an exploratory subgroup analysis, we will report all primary and secondary 
outcomes stratified by type of DOAC (i.e. apixaban, betrixaban, dabigatran, 
edoxaban, or rivaroxaban) if the number of cases is sufficient. In addition, we will 
perform a subgroup analysis for patients who were diagnosed with APS compared to 
patients who do not have APS. No formal statistical comparisons will be performed for 
these subgroup analyses.  
 
6.2 Secondary study parameter(s)  
All secondary outcomes will be analysed with the same method as used for the main 
analysis. Confounders to be included in each propensity score calculation are detailed in 
Appendix C. Outcomes regarding the post-CVT residual symptoms and two-year VTE 
recurrence rate will be reported descriptively.  
 
 
 

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7. ETHICAL CONSIDERATIONS 
7.1 Regulation statement 
This study will be conducted in accordance with the principles of the Declaration of 
Helsinki, as amended by the World Medical Association General Assembly in October 
2013, and with the guidelines for Good Clinical Practice. 
 
7.2 Recruitment and consent 
The study uses only data that are collected as part of routine care. The local 
investigator at each participating center will inform eligible subjects of the study. All 
patients or their proxy’s will be asked for written informed consent to allow use of their 
data in a coded manner in accordance with the European Union General Data 
Protection Regulation (GDPR) and other applicable laws for that particular hospital.  
 
7.3 Benefits and risks assessment 
This study poses no risk and no burden to participants. Only existing patient care 
data will be used. 
 
 

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8. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
8.1 Handling, storage, and maintenance of data and documents 
All patients will be assigned a unique study ID which contains no identifying 
information. Study data will be entered into the study database under this unique 
study ID by the local investigator. The study database will not contain directly 
identifying data such as name, address or date of birth. The subject identification 
code list linking the study ID with the source data remains at the local hospital and is 
stored by the local investigator separate from the study database. Only local 
investigators participating in the registry will have access to this list.  
The study data will be kept for a minimum of 15 and a maximum of 25 years 
(conform the local requirements) after enrollment of the last patient into the registry.  
 
The Amsterdam UMC will function as the controller of the data for this study. Castor 
Electronic Data Capture system will be used to collect all data in a standardized 
manner (www.castoredc.com). Amsterdam UMC has a data processor agreement 
with Castor EDC. Each center should comply with local laws and institutional rules 
regarding data storage and data transfer, sign the Data Transfer Agreement, and 
send the local IRB approval to the Study Coordinator before enrollment can start. 
Additional Data Transfer Agreements for the execution of substudies will be 
prepared as necessary. 
 
8.2 Study Oversight 
The project leader has the final responsibility for the execution of the DOAC-CVT 
study. The Steering Committee will oversee the conduction of the study and provide 
support and guidance. The Steering Committee will meet twice a year, either in 
person or digitally. Additional Steering Committee meetings may be scheduled at 
the request of the Executive Committee. A national leader will be appointed by the 
Executive Committee for each country that participates in the study, and all national 
leaders are members of the Steering Committee. The Executive Committee 
supervises the day-to-day study execution for the Steering Committee. The day-to-
day study execution will be coordinated by the study coordinator. 
 
 
 
 
 
 

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Executive Committee 
Dr. Jonathan Coutinho (project leader) 
Amsterdam UMC, Amsterdam, the Netherlands  
Dr. Jukka Putaala 
Helsinki University Hospital, Helsinki, Finland 
Prof. Jose Ferro 
Hospital da Luz, University of Lisbon, Lisbon, Portugal 
Prof. Turgut Tatlisumak 
Sahlgrenska University Hospital, Gothenburg, Sweden 
Dr. Diana Aguiar de Sousa 
Centro Hospitalar Universitário Lisboa Central (ULS São José), Lisbon, Portugal 
Dr. Katarina Jood 
Sahlgrenska University Hospital, Gothenburg, Sweden 
 
 
Steering Committee 
Dr. Jonathan Coutinho  
Amsterdam UMC, Amsterdam, the Netherlands 
Dr. Jukka Putaala 
Helsinki University Hospital, Helsinki, Finland 
Prof. Jose Ferro 
Hospital da Luz, University of Lisbon, Lisbon, Portugal 
Prof. Turgut Tatlisumak 
Sahlgrenska University Hospital, Gothenburg, Sweden 
Drs. Mayte Sanchez van Kammen 
Amsterdam UMC, Amsterdam, the Netherlands 
Drs. Anita van de Munckhof 
Amsterdam UMC, Amsterdam, the Netherlands 
Dr. Diana Aguiar de Sousa 
Centro Hospitalar Universitário Lisboa Central (ULS São José), Lisbon, Portugal 
Dr. Katarina Jood 
Sahlgrenska University Hospital, Gothenburg, Sweden 
All national leaders (see Appendix D)  
 
Independent Adjudication Committee 
Prof. Saskia Middeldorp, chair 
Radboud UMC, Nijmegen, the Netherlands 
Prof. Lia Neto  
Hospital de Santa Maria, Lisbon, Portugal 
Prof. Marcel Arnold 
Bern University Hospital, Bern, Switzerland 
 

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8.3 Public disclosure and publication policy 
This study is registered at clinicaltrials.gov and the study protocol has been 
published in a peer-reviewed journal.25 A first draft of the main study paper will be 
drafted by the Executive Committee together with a PhD student. All Steering 
Committee members will be co-authors on the main study paper. All other 
investigators will be listed on the main study paper as members of the DOAC-CVT 
study group. In addition, participating centres may contribute one additional co-
author after inclusion of 10 patients, and an additional co-author for each additional 
20 patients included afterwards. All authors must fulfil the ICMJE criteria for 
scientific authorship. After publication of the primary study results, each participating 
investigator may submit proposals for a substudy to the Executive Committee. After 
approval by the Executive Committee, the local investigator of that hospital may take 
the lead in the execution and authorship of that particular substudy. 
 
 

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1. Silvis SM, de Sousa DA, Ferro JM, Coutinho JM. Cerebral venous thrombosis. Nat Rev 
Neurol. 2017;13(9):555-565. doi:10.1038/nrneurol.2017.104 
2. Ferro JM, Canhao P, Stam J, Bousser MG, Barinagarrementeria F. Prognosis of cerebral 
vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and 
Dural Sinus Thrombosis (ISCVT). Stroke. Mar 2004;35(3):664-70. 
doi:10.1161/01.Str.0000117571.76197.26 
3. Coutinho JM, Zuurbier SM, Stam J. Declining mortality in cerebral venous thrombosis: a 
systematic review. Stroke. May 2014;45(5):1338-41. doi:10.1161/STROKEAHA.113.004666 
4. Coutinho J, de Bruijn SF, Deveber G, Stam J. Anticoagulation for cerebral venous sinus 
thrombosis. The Cochrane database of systematic reviews. Aug 10 2011;(8):Cd002005. 
doi:10.1002/14651858.CD002005.pub2 
5. Ferro JM, Bousser MG, Canhao P, et al. European Stroke Organization guideline for the 
diagnosis and treatment of cerebral venous thrombosis - endorsed by the European 
Academy of Neurology. Eur J Neurol. Oct 2017;24(10):1203-1213. doi:10.1111/ene.13381 
6. Saposnik G, Barinagarrementeria F, Brown RD, Jr., et al. Diagnosis and management of 
cerebral venous thrombosis: a statement for healthcare professionals from the American 
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doi:10.1161/STR.0b013e31820a8364 
7. Foerch C, Lo EH, van Leyen K, Lauer A, Schaefer JH. Intracerebral Hemorrhage 
Formation Under Direct Oral Anticoagulants. Stroke. Apr 2019;50(4):1034-1042. 
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8. Vinogradova Y, Coupland C, Hill T, Hippisley-Cox J. Risks and benefits of direct oral 
anticoagulants versus warfarin in a real world setting: cohort study in primary care. BMJ. Jul 
4 2018;362:k2505. doi:10.1136/bmj.k2505 
9. 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. Sep 3 2019;doi:10.1001/jamaneurol.2019.2764 
10. 
Lurkin A, Derex L, Fambrini A, Bertoletti L, Epinat M, Mismetti P, Dargaud 
Y. Direct Oral Anticoagulants for the Treatment of Cerebral Venous Thrombosis. 
Cerebrovascular diseases (Basel, Switzerland). 2019;48(1-2):32-37. doi:10.1159/000502454 
11. 
Rusin G, Wypasek E, Papuga-Szela E, Żuk J, Undas A. Direct oral 
anticoagulants in the treatment of cerebral venous sinus thrombosis: a single institution's 
experience. Neurologia i neurochirurgia polska. 2019;53(5):384-387. 
doi:10.5603/PJNNS.a2019.0037 
12. 
Wasay M, Khan M, Rajput HM, et al. New Oral Anticoagulants versus 
Warfarin for Cerebral Venous Thrombosis: A Multi-Center, Observational Study. J Stroke. 
May 2019;21(2):220-223. doi:10.5853/jos.2019.00150 
13. 
Lee GKH, Chen VH, Tan CH, et al. Comparing the efficacy and safety of 
direct oral anticoagulants with vitamin K antagonist in cerebral venous thrombosis. J Thromb 
Thrombolysis. Apr 11 2020;doi:10.1007/s11239-020-02106-7 
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Yaghi S, Shu L, Bakradze E, et al. Direct Oral Anticoagulants Versus 
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International Study. Stroke. Mar 2022;53(3):728-738. doi:10.1161/STROKEAHA.121.037541 
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Anticoagulation With Rivaroxaban to Standard-of-Care in Symptomatic Cerebral Venous 
Thrombosis. Stroke. Nov 2023;54(11):2724-2736. doi:10.1161/STROKEAHA.123.044113 
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Hiltunen S, Putaala J, Haapaniemi E, Tatlisumak T. Long-term outcome 
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Koopman K, Uyttenboogaart M, Vroomen PC, van der Meer J, De Keyser 
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Dentali F, Poli D, Scoditti U, et al. Long-term outcomes of patients with 
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2012;10(7):1297-302. doi:10.1111/j.1538-7836.2012.04774.x 
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Schulman S, Kearon C. Definition of major bleeding in clinical 
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Haemost. Apr 2005;3(4):692-4. doi:10.1111/j.1538-7836.2005.01204.x 
20. 
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. Nov 2015;13(11):2119-26.  
21. 
Aguiar de Sousa D, Lucas Neto L, Arauz A, et al. Early Recanalization in 
Patients With Cerebral Venous Thrombosis Treated With Anticoagulation. Stroke. Apr 
2020;51(4):1174-1181. doi:10.1161/strokeaha.119.028532 
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Winstein CJ, Stein J, Arena R, et al. Guidelines for Adult Stroke 
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van de Munckhof A, Sanchez van Kammen M, Krzywicka K, et al. Direct 
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doi:10.3389/fneur.2023.1251581 
 
 
 
 
 

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APPENDIX A.  
Standard Operating Procedure for the Scoring of Cerebral Venous Recanalization 
[Standard Operating Procedure for Recanalization Assessment]  
 
APPENDIX B.  
ISTH definitions of major and clinically relevant non-major bleeding 
 
Major bleeding19 
Symptomatic presentation and 
- 
Fatal bleeding, and/or 
- 
Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intra‐articular or pericardial, or intramuscular with 
compartment syndrome, and/or 
- 
Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more, or 
leading to transfusion of two or more units of whole blood or red cells 
 
Clinically relevant non-major bleeding20 
Any sign or symptom of hemorrhage (e.g., more bleeding than would be expected for a 
clinical circumstance, including bleeding found by imaging alone) that does not fit the 
criteria for the ISTH definition of major bleeding but does meet at least one of the following 
criteria: 
- 
Requiring medical intervention by a healthcare professional 
- 
Leading to hospitalization or increased level of care 
- 
Prompting a face to face (i.e., not just a telephone or electronic communication) 
evaluation 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX C.  
All secondary outcomes at 6 months will be analysed with the same method as used in 
the main analysis. Confounders to be included in each propensity score calculation are 
listed below per outcome: 
 
 
Figure 6. Directed Acyclic Graph depicting factors influencing anticoagulant treatment choice 
and risk of recurrent venous thrombotic event  
 
Symptomatic recurrent VTE rate (Figure 6) 
• 
Age at time of CVT diagnosis 
• 
GCS at CVT diagnosis 
• 
Previous VTE 

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Figure 7. Directed Acyclic Graph depicting factors influencing anticoagulant treatment choice 
and risk of major or clinically relevant non-major bleeding 
 
Major bleeding rate14 (Figure 7)  
• 
Age at CVT diagnosis 
• 
CNS infection concurrent with the index CVT 
• 
ICH at CVT diagnosis, or after diagnosis but before start of oral anticoagulant 
treatment 
• 
Previous major bleeding prior to the index CVT (according to ISTH criteria)14 
 
Clinically relevant non-major bleeding rate15 (Figure 7) 
• 
Age at CVT diagnosis 
• 
CNS infection concurrent with the index CVT 

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• 
ICH at CVT diagnosis, or after diagnosis but before start of oral anticoagulant 
treatment 
• 
Previous major bleeding prior to the index CVT (according to ISTH criteria)14 
 
 
Figure 8. Directed Acyclic Graph depicting factors influencing anticoagulant treatment choice 
and risk of death or dependency2 
 
All-cause mortality (Figure 8) 
• 
Age at CVT diagnosis 
• 
CNS infection concurrent with the index CVT 
• 
GCS at CVT diagnosis 
• 
ICH at CVT diagnosis, or after diagnosis but before start of oral anticoagulant 
treatment 

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Modified Rankin Scale score (Figure 8) 
• 
Age at CVT diagnosis 
• 
CNS infection concurrent with the index CVT 
• 
GCS at CVT diagnosis 
• 
ICH at CVT diagnosis, or after diagnosis but before start of oral anticoagulant 
treatment 
 
Figure 9. Directed Acyclic Graph depicting factors influencing anticoagulant treatment choice 
and risk of arterial thrombotic event 
 
Arterial thrombotic events (Figure 9) 
• 
Age at CVT diagnosis 
• 
History of hypertension (as determined by treating physician) 

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Figure 10. Directed Acyclic Graph depicting factors influencing anticoagulant treatment choice 
and cerebral venous recanalization17 
 
Cerebral venous recanalization rate (Figure 10) 
• 
Age at CVT diagnosis 
• 
Sex 
• 
Isolated superior sagittal sinus thrombosis at diagnosis 
 
 

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APPENDIX D.  
List of National Leaders of the DOAC-CVT study  
 
Country 
National Leader 
E-mail address 
Argentina 
Matías Alet 
matias.alet@gmail.com 
Australia 
Timothy J. Kleinig 
timothy.kleinig@sa.gov.au 
Belgium 
Robin Lemmens 
robin.lemmens@uzleuven.be 
Brazil 
Adriana B. Conforto 
adriana.conforto@gmail.com 
Chile 
Daniel Galdames Contreras 
dgaldames@hcuch.cl 
China 
Xunming Ji 
jixm@ccmu.edu.cn 
Costa Rica 
Miguel A. Barboza 
miguel.barboza_e@ucr.ac.cr 
Finland 
Jukka Putaala 
jukka.putaala@hus.fi 
Germany 
Sven Poli 
sven.poli@uni-tuebingen.de 
India 
Sanjith Aaron 
drsanjith@yahoo.co.uk 
Israel 
Ronen R. Leker 
leker@hadassah.org.il 
Italy 
Francesco Dentali 
fdentali@libero.it 
Mexico 
Antonio Arauz 
antonio.arauz@prodigy.net.mx 
the Netherlands Jonathan M. Coutinho 
j.coutinho@amsterdamumc.nl 
New Zealand 
Teddy Wu 
teddyyhwu@gmail.com 
Norway 
Espen S. Kristoffersen 
e.s.kristoffersen@medisin.uio.no 
Pakistan 
Mohammad Wasay 
mohammad.wasay@aku.edu 
Portugal 
Diana Aguiar de Sousa 
dianasousa@campus.ul.pt 
Romania 
Florina Antochi 
flrant@yahoo.com 
Spain 
María Hernandez-Perez 
mhernandez@igtp.cat 
Sweden 
Katarina Jood 
katarina.jood@neuro.gu.se 
Switzerland 
Mirjam R. Heldner 
mirjam.heldner@insel.ch 
Turkey 
Nilufer Yesilot 
niluferyes@yahoo.com 
United States 
Wayneho Kam 
wayneho.kam@duke.edu