Transvenous embolization for intracranial arteriovenous malformations: study protocol for a prospective, single-center cohort trial
Yan-Yan He, Tian-Xiao Li, Wei-Xing Bai, Ying-Kun He, Bin Xu, Xiao-Yu Kang, Jiang-Yu Xue
Department of Intracranial Arteriovenous Malformation, Zhengzhou University People's Hospital, Zhengzhou, Henan Province, China
|Date of Web Publication||15-May-2018|
Department of Intracranial Arteriovenous Malformation, Zhengzhou University People's Hospital, Zhengzhou, Henan Province
Source of Support: This study was supported by the National Natural Science Foundation of China, No. 81601583., Conflict of Interest: None
Background and objectives: In 2010, Nguyen et al. reported a novel method for the treatment of intracranial arteriovenous malformations by transvenous embolization combined with conventional treatment. At present, although the outcome of this approach is generally good, most studies are case reports, and there is a lack of prospective cohort study for assessing the effectiveness of this method. Therefore, in this clinical trial protocol, we will assess the efficacy of transvenous embolization of draining venous unit, with the aim of helping to optimize treatment strategies for patients with intracranial arteriovenous malformations.
Design: This is a prospective, single-center cohort study.
Methods: We will recruit 190 patients with intracranial arteriovenous malformations from the Department of Intracranial Arteriovenous Malformation, Henan Provincial People's Hospital, China. The patients will be assigned to two groups. Participants in the control group (n = 95) will undergo conventional treatment, such as surgery, stereotactic radiosurgery and transarterial embolization. Participants in the trial group (n = 95) will receive transvenous embolization combined with conventional treatment.
Outcome measures: The primary outcome measures are stroke or death within 30 days of surgery, and efficacy of treatment at 6 months postoperatively. The secondary outcome measures are the efficacy of treatment at 30 days and 24 months postoperatively, National Institutes of Health Stroke Scale scores, modified Rankin Scale scores at 1, 7 and 30 days and 3, 6, 12, 24 and 36 months postoperatively, and adverse reactions during treatment and follow-up.
Discussion: Our study will provide clinical evidence for the rational use of transvenous embolization for intracranial arteriovenous malformations.
Ethics and dissemination: This trial has been approved by the Medical Ethics Committee of Henan Provincial People's Hospital of China [approval number: 2017 (41)]. This trial was designed in 1 August 2017. Ethics approval was completed in 19 October 2017. This trial was registered in 11 December 2017. The recruitment of participants began in January 2018. The recruitment will be finished in January 2019. Follow-up will be completed in January 2022. Data analysis will be finished in January 2023.
Trial registration: This trial had been registered in the Chinese Clinical Trial Registry (registration number: ChiCTR-OOC-17013851). Protocol version (1.0).
Keywords: intracranial arteriovenous malformations; transvenous embolization; National Institutes of Health Stroke Scale scores; modified Rankin Scale scores; cohort study
|How to cite this article:|
He YY, Li TX, Bai WX, He YK, Xu B, Kang XY, Xue JY. Transvenous embolization for intracranial arteriovenous malformations: study protocol for a prospective, single-center cohort trial. Asia Pac J Clin Trials Nerv Syst Dis 2018;3:27-32
|How to cite this URL:|
He YY, Li TX, Bai WX, He YK, Xu B, Kang XY, Xue JY. Transvenous embolization for intracranial arteriovenous malformations: study protocol for a prospective, single-center cohort trial. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2018 [cited 2018 May 22];3:27-32. Available from: http://www.actnjournal.com/text.asp?2018/3/2/27/232078
| Introduction|| |
Intracranial arteriovenous malformations (AVMs) are congenital abnormalities of the cerebral blood vessels that form during the fetal period. Intracranial AVMs are abnormal tangles of blood vessels connecting arteries and veins. The hemodynamics of these malformations is extremely complex. Intracranial AVMs are common in adolescents, and the main symptoms are cerebral hemorrhage and epilepsy (Solomon and Connolly, 2017). When these vascular tangles (nidus) break, intracranial hematoma and cerebral hernia may occur. The treatment of intracranial AVMs is based on the vascular architecture, location and clinical symptoms of the lesion, and generally includes minimally invasive surgical resection, endovascular embolization and stereotactic radiosurgery. However, the efficacy of the various treatment methods varies (Derdeyn et al., 2017). Nguyen et al. (2010) created a method for the treatment of intracranial AVMs by transvenous embolization, and this method has been validated by a number of clinical studies (Kessler et al., 2011; Cooke et al., 2012; Consoli et al., 2013; Trivelato et al., 2014; Orlov et al., 2015; Mendes et al., 2016; Bai et al., 2017; He et al., 2017; Viana et al., 2017). Iosif et al. (2015) and a subsequent study by their team (Bai et al., 2018) reported follow-up for 6 months and 30 days in 20 and 6 patients, respectively, and the efficacies were good in most patients [Table 1]. However, these studies are primarily case reports, and a standardized large-sample long-term follow-up trial for transvenous embolization for draining vein obliteration has not yet been conducted.
|Table 1: Clinical studies regarding transvenous embolization for treatment of intracranial arteriovenous malformations (AVMs)|
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Novelty of this study
This trial will be the first prospective cohort study on transvenous embolization of draining venous unit for treating intracranial AVMs, with the aim of helping to optimize individualized treatment of intracranial AVMs using the preoperative evaluation system.
This trial will assess the efficacy of transvenous embolization of draining venous unit combined with conventional methods for intracranial AVMs with the aim of providing a rational basis for the development of optimal treatment strategies.
| Methods/Design|| |
For this prospective cohort study, we will recruit 190 patients with intracranial AVMs from Henan Provincial People's Hospital, China. The patients will be divided into two groups. Participants in the control group (n = 95) will undergo conventional treatment, such as surgery, stereotactic radiosurgery and transarterial embolization. Participants in the trial group (n = 95) will receive transvenous embolization combined with conventional treatment. The primary outcome measures are stroke or death within 30 days of surgery, and efficacy of treatment at 6 months postoperatively. The secondary outcome measures are the efficacy of treatment at 30 days and 24 months postoperatively, National Institutes of Health Stroke Scale (NIHSS) scores, modified Rankin Scale (mRS) scores at 1, 7 and 30 days and 3, 6, 12, 24 and 36 months postoperatively, and adverse reactions during treatment and follow-up. These indicators will be used to assess the efficacy of transvenous embolization combined with conventional treatment.
Physicians from the Outpatient Clinic and Inpatient Department of Intracranial Arteriovenous Malformation, Henan Provincial People's Hospital of China will recruit patients to participate in this trial. Patients will be provided trial information, and written informed consent will be obtained from patients and legal representatives prior to inclusion. Patients and legal representatives will be explicitly informed that they can withdraw from the trial at any time, and withdrawal from the trial will not affect their subsequent treatment.
Intracranial AVM patients from the Department of Intracranial Arteriovenous Malformation, Henan Provincial People's Hospital of China will be recruited.
Patients who meet all of the following criteria will be considered for study inclusion:
- Diameter of nidus ≤ 6 cm
- Nidus have ruptured and bled before surgery
- Tolerance to hypotension
- Age 6–60 years
- Provision of written informed consent by patients or legal representatives
Patients who meet one or more of the following conditions will be excluded from the study:
- Multiple AVMs, venous malformations, cavernous hemangioma, hereditary hemorrhagic telangiectasia, moyamoya disease
- Although the patients are medically treated, they cannot tolerate general anesthesia
- Blood vessels are severely distorted, making it mechanically difficult for the arterial sheath and guiding catheter to reach the internal carotid artery or vertebral artery
- Thrombosis in the vessel wall near or at the lesion site
- History of severe allergies to contrast or other nonadhesive embolic agents
- Uncontrolled active bleeding
- History of major surgery within 30 days before surgery (including femoral artery or aortic opening surgery) or plan to perform major surgery within 90 days
- Severe dementia or mental disorder
- Combination with other diseases, life expectancy < 3 years.
- Participation in another clinical trial
Patients who meet one or more of the following conditions will be withdrawn from the study:
- Incomplete data that affect efficacy or safety evaluation
- Complications affecting efficacy and safety assessment and diseases affecting outcomes during the trial
Upon admission, the patients will be divided into trial and control groups, with 95 patients in each group.
In the control group, conventional approaches will be used, such as surgery, stereotactic radiosurgery, transarterial embolization, and various combinations of these methods. All treatment protocols will be standardized (Starke et al., 2009; Diaz and Scranton, 2016; Singh, 2017).
In the trial group, participants will receive transarterial embolization. After general anesthesia, changes in blood pressure will be continually monitored. Internal jugular vein puncture will be conducted under ultrasound guidance. One or two catheters will be introduced from the venous, and placed as close to the nidus as possible with the micro guidewire and guide catheter. Using the “pressure cooker technique” (Chapot et al, 2014; Zhang et al., 2017), the embolic agent will be injected from the venous to the nidus. Intermittent arterial angiography will be performed to confirm embolization of the nidus and their subsequent disappearance, and to observe any remaining residual lesions. Based on the vascular architecture of the malformation (nidus), standard treatment options can be combined before and after transvenous embolization of draining venous unit.
Primary outcome measure
- Stroke or death within 30 days of surgery.
- Efficacy of treatment at 6 months postoperatively. During the visit, the appearance of the deformed tangle of blood vessels (nidus) on MRI (Siemens 3.0T, Germany) and digital subtract angiography (Philips, Netherlands) will be categorized as follows: resolved—the nidus have completely disappeared; improvement—residual nidus are smaller than before; stable—residual nidus have not changed; progression—residual nidus are larger than before. The first three categories are considered to indicate effectiveness. Efficacy of treatment is the ratio of the number of patients who are effectively treated to the total number of patients.
Secondary outcome measures
- Efficacy of treatment at 30 days and 24 months post-operatively.
- NIHSS scores at 1, 7 and 30 days and 3, 6, 12, 24 and 36 months postoperatively. This scale is mainly used to assess neurological deficit, with a total score of 42. The higher the score, the more severe the neurological deficit (Dunning, 2011).
- mRS scores at 1, 7 and 30 days and 3, 6, 12, 24 and 36 months postoperatively. This scale is commonly used for measuring the degree of disability. The scale runs from 0–6, from perfect health without symptoms to death. The higher the score, the worse the prognosis (Wilson et al., 2002).
- Adverse reactions during treatment and follow-up: Adverse reactions include all unfavorable medical events that occur during treatment and follow-up, and whether the adverse reaction is associated with the treatment. Any complications (including the nervous system and non-nervous system) that cause patients to die within 30 days after surgery are considered as the factors for “operation-related” deaths (Jayaraman et al., 2012). If neurological dysfunction caused by focal ischemia in the brain, spinal cord or retina lasts for more than 24 hours or a new cerebral infarction is shown by magnetic resonance imaging, investigators need to deal with adverse events. The details of the measures taken to manage adverse events will be recorded in the original documents and case report forms. Proper therapeutic measures will be taken if a severe adverse event occurs, to protect the rights and interests of the participants. If necessary, the Ethics Committee will have the right to terminate the trial immediately. At the end of the trial, the participants, sponsors, Ethics Committee, provincial, municipal and China Food and Drug Administration will be informed of the adverse events and their causes and explanations. In addition, the adverse events will be reported to the provincial, municipal and China Food and Drug Administration within 24 hours. Simultaneously, we will inform other medical institutions that carry out the clinical trial of the medical device.
[Figure 1] shows the flow chart of the study protocol. The schedule of outcome assessments is shown in [Table 2].
The complications of conventional methods for treating intracranial AVMs is approximately 7.4%, and the expected complications of conventional methods combined with transvenous embolization is approximately 2.5%. Taking 1 - β = 0.8 with a significance level of α = 0.05, the final effective sample size of n = 71 per group will be calculated using PASS 11.0 software (PASS, Kaysville, UT, USA). If we assume a loss rate of 20%, we will require 86 cases per group. We will include 190 cases (n = 95 per group).
Statistical analysis will be performed using SPSS 22.0 software (IBM, Armonk, NY, USA), and will be expressed as mean ± standard deviation, median, minimums, maximums, lower quartile (q1) and upper quartiles (q3). Data will be analyzed using paired t-test or Wilcoxon's rank sum test. Categorical variables will be represented by the number of cases and the percentage. Two-tailed tests will be adopted. A value of P < 0.05 will be considered statistically significant.
Data collection and management
All clinical and other relevant data of the patients will be faithfully recorded on the case report form, which will be kept secretly by the special person. The Hospital Ethics Committee is responsible for supervising the testing process and data. Once an adverse event occurs, it will be immediately reported to the committee, and the committee will determine whether the trial will continue. The original data can be obtained by contacting the corresponding author.
The auditor will be responsible for confirming whether all the contents of the research program are strictly observed and the records and reports of all data are correct. All researchers will strictly implement the standard operating procedures for clinical trials and undergo unified training to unify the recording methods and criteria. The case report form will be truthfully and carefully recorded in detail to ensure that the case report form is complete, authentic and reliable.
We will reimburse each patient's travel expenses during the trial. Patients participating in the trial will receive free registration and laboratory examinations included in the study protocol during follow-up. The trial provides insurance coverage for the patient's intervention in China Life Insurance (Group) Company with the Insurance Application Number: 700444J-7004470. The insurance company will bear the treatment cost and corresponding financial compensation for the participant who suffers the test-related damage or death.
Ethics and dissemination
This trial has been approved by the Medical Ethics Committee of Henan Provincial People's Hospital of China [approval number: 2017 (41)] (Additional file 1 [Additional file 1]). Written informed consent will be obtained from patients and legal representatives. The whole process will be supervised by the ethics committee. The writing and editing of the article will be performed in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) (Additional file 2 [Additional file 2]). The results of the trial will be reported in a scientific conference or disseminated in a peer-reviewed journal. Anonymized trial data will be available indefinitely at www.figshare.com.
| Discussion|| |
Contributions and problems of previous studies in this field
Transvenous embolization combined with conventional methods for treating intracranial AVMs is a new treatment method described in 2010 (Nguyen et al., 2010). This method has been extensively used in the clinic, and can effectively reduce and eliminate deformed vascular tangles (nidus). The emergence of new embolic materials such as Onyx, due to its low adhesiveness, can appropriately extend the injection time, thus improving the controllability of intraoperative thrombosis, penetration and reflux of the gel in the lesion. The use of pressure cooker technology can resist embolic agent reflux, making nidus in transvenous embolization effective and controllable (Panagiotopoulos et al., 2009). However, there is still a lack of prospective cohort study for this method.
Characteristics of this study protocol
This will be the first prospective cohort study to evaluate the efficacy of transvenous embolization combined with conventional methods for treating intracranial AVMs. Our findings will provide evidence on the safety and efficacy of transvenous embolization for draining venous unit.
Limitations of this study
Surgery, stereotactic radiosurgery and transarterial embolization will be used in this trial; however, the efficacies of these methods may not be consistent, thereby introducing variability into the analysis.
Significance of this study protocol
The trial will provide objective data on the safety and efficacy of transvenous embolization combined with conventional methods for the treatment of intracranial AVMs, and should help in optimizing treatment strategies for patients.
| Trial Status|| |
This trial was designed on August 1, 2017. Ethics approval was completed on October 19, 2017. This trial was registered on December 11, 2017. The recruitment of participants began in January 2018. The recruitment will be finished in January 2019. Follow-up will be completed in January 2022. Data analysis will be finished in January 2023. Patient recruitment is ongoing.
Additional file 1: Ethical approval document.
Additional file 2: SPIRIT checklist.
We are very grateful to Professor Charbel Mounayer and Professor Isil Saatci for preoperative electronic consultation.
Study design: TXL, WXB, YKH, BX, XYK and JYX. Manuscript writing: YYH and YKH. Proofreading: TXL, WXB and JYX.
This study was supported by the National Natural Science Foundation of China, No. 81601583. The funding bodies play no role in the study design, in the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the article for publication.
Conflicts of interest
The authors declare that the research will be conducted in the absence of any commercial or financial relationships that can be construed as a potential conflict of interest.
Institutional review board statement
All protocols will be performed in accordance with the ethical principles of the Declaration of Helsinki. This trial has been approved by the Medical Ethics Committee of Henan Provincial People's Hospital of China [approval number: 2017 (41)].
Declaration of patient consent
The authors certify that they will obtain all appropriate patient or their legal guardian consent forms. In the form the patients or their legal guardians will give their consent for patients’ images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
This study follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidance for protocol reporting.
The statistical methods of this study were reviewed by the biostatistician of Zhengzhou University People's Hospital, China.
Copyright transfer agreement
The Copyright License Agreement has been signed by all authors before publication.
Data sharing statement
Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices) will be in particular shared. Study protocol and informed consent form will be available within 6 months after completion of the trial. Results will be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal. Anonymized trial data will be available indefinitely at www.figshare.com.
Checked twice by iThenticate.
Externally peer reviewed.
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[Table 1], [Table 2]