TransRadial versus transfemoral Access for CErebral angiography (TRACE): study protocol for a multicenter randomized trial

Introduction

Cerebral angiography is the gold standard for diagnosing cerebrovascular diseases. Traditionally, it has performed primarily via transfemoral access (TFA). However, TFA presents significant drawbacks, including the need for costly closure devices, prolonged immobilization, and a high risk of complications such as venous thrombosis, hematomas, and nerve damage (1,2). These issues highlight the urgent need for optimizing access pathways in cerebral angiography.

Transradial access (TRA) is a newer approach to interventional procedures. First reported by Campeau in 1989 for coronary angiography (3), TRA has since gained widespread use in diagnosing and treating cardiovascular diseases. In the cardiovascular field, TRA has gradually replaced TFA as the preferred arterial route. Owing to its advantages of lower hospital costs, shorter hospital stays, greater patient acceptance and satisfaction, and a reduced complication rate (4). Inspired by these benefits, TRA has also been adopted in cerebrovascular angiography and interventions. Compared to TFA, TRA is less invasive, easier to manage hemostatically and associated with lower complication rates and shorter bed rest, making it particularly popular in coronary interventions. Recent studies have confirmed the feasibility and safety of using TRA for cerebrovascular procedures (5-8). Nonetheless, due to a lack of relevant materials and experience, TRA remains an alternative rather than the primary approach for cerebral angiography.

With advancements in neurointerventional techniques and materials, TRA has become increasingly utilized for cerebral angiography and interventions. Recent studies indicate that there is no significant difference in the success rate of complete cerebral angiography diagnoses between TRA and TFA (9,10). More importantly, TRA outperforms TFA in terms of shorter hospital stays, lower complication rates, and greater patient comfort (10). However, subtle neurological complications, such as microembolic events, may be overlooked without early post-procedural magnetic resonance imaging (MRI), as demonstrated by a short protocol [diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) sequences] performed 2–4 hours after angiography (11). Despite these findings, due to the lack of high-quality clinical research providing robust evidence, TRA remains an alternative option, primarily used when TFA is not feasible or presents challenges, and it has not yet been widely applied.

Therefore, the randomized trial aimed to compare the safety and efficacy of TRA and TFA in cerebral angiography, which will provide high-level evidence to support the broader application of TRA in cerebral angiography. We present this article in accordance with the SPIRIT reporting checklist (available at https://jni.amegroups.com/article/view/10.21037/jni-24-9/rc).

Methods

Study aims

This study aims to compare the safety and efficacy of TRA versus TFA for diagnostic cerebral angiography in Chinese population.

Study design

TransRadial versus transfemoral Access for CErebral angiography (TRACE) is an investigator-initiated, multicenter, prospective, controlled, non-inferiority study, assessing whether the success rate of diagnostic cerebral angiography via TRA is not inferior to that via TFA. Participants will be randomly assigned to either the control group (TRA angiography) or the intervention group (TFA angiography). The study flow diagram is shown in Figure 1. Follow-up would be conducted at 1 and 30 days after randomization (Table 1).

Figure 1 CONSORT flow diagram. TFA, transfemoral access; TRA, transradial access; VAS, Visual Analogue Scale.

Investigators must thoroughly explain the details of the clinical trial, including known, foreseeable risks and possible adverse events (AEs), etc., to the subjects or to the guardians of subjects without capacity for civil conduct. Eligible patients are informed in person by clinicians and given information materials. Participants must read the information sheet and sign the informed consent form before participating in this study.

Population

This multicenter, investigator-initiated trial (IIT) will be conducted at 13 sites across China. Each site is required to perform cerebral angiography via both TRA and TFA. Investigators must have independently completed more than 50 cases of TRA angiography and more than 200 cases of TFA angiography independently. The full list of trial sites, principal investigators and additional trial staff is provided in Appendix 1. Detailed inclusion and exclusion criteria are shown as below.

Inclusion criteria

• Age between 18 and 80 years old;
• Scheduled to undergo diagnostic cerebral angiography;
• Suitable for cerebral angiography via TRA and TFA access, with a radial artery diameter ≥2 mm confirmed by ultrasonography;
• Modified Rankin Scale (mRS) score ≤2;
• Provided written informed consent.

Exclusion criteria

• Severe stenosis of the radial, brachial, subclavian, brachiocephalic, iliac or common femoral arteries, or any significant vascular disease (such as aortic aneurysm, etc.) that may obstruct guidewire passage;
• Arteriovenous fistula for hemodialysis present in the right upper limb;
• Planned interventional surgery within 24 hours of the initial study angiography;
• Requirement for cerebral angiography in an emergency department;
• Use of general anesthesia;
• Any contraindication to cerebral angiography, such as allergy or intolerance to the contrast media, uncorrected severe coagulation disorders, arterial dissection in the target vessel, puncture site infection, or renal insufficiency [creatinine (Cr) >3 times of the upper limit of normal (ULN)], etc.;
• Women who are pregnant or planning to become pregnant within 1 year;
• Participation in another clinical trial;
• Any other condition deemed unsuitable for participation by the investigator.

Randomization and blinding

After screening for inclusion and exclusion criteria, subjects will be randomized into the intervention group (TRA angiography) or the control group (TFA angiography) at the ratio of 1:1 through a computerized central randomization system.

As this is an open-label trial, patients and investigators will be aware of the treatment allocation after randomization, blinding is not possible. The design is open label with only outcome assessors being blinded. Neuroimaging will also be reviewed by a core laboratory that is unaware of the treatment allocation. The treatment allocation information will be kept separate from the main study database. The steering committee will remain unaware of the interim efficacy and safety analysis results. An independent statistician from the Data and Safety Monitoring Board (DSMB) will integrate data on treatment allocation with clinical data to report to the DSMB.

Intervention

Patients in the Control group will be performed standard cerebrovascular angiography via TFA. Standard cerebrovascular angiography involves imaging the aortic arch and super-selective angiography of its branch arteries, including bilateral internal carotid arteries, common carotid arteries, and vertebral arteries. In addition, super-selective angiography of the target vessels should be performed to ensure an accurate diagnosis.

Patients assigned to the intervention group will receive standard cerebrovascular angiography via TRA. The requirement of cerebrovascular angiography is the same as the control group.

Ethical declaration

The study will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics review committee of Huashan Hospital, Fudan University (No. 2023502) and ethics committee at each participating hospital. Informed consent will be obtained from all individual participants or their surrogates.

Results

Primary outcome

The primary outcome of this study is the rate of successful diagnostic cerebral angiography, defined as the successful superselection of the aortic arch vessel without changing the arterial approach, with angiography results meeting diagnostic requirements. Any change in arterial approach before or during the procedure would be considered as a diagnosis failure.

Secondary outcomes

The secondary outcomes are as follows: (I) the rate of successful accurate diagnosis; (II) the duration of angiography; (III) the duration of fluoroscopy; (IV) the bedridden time; (V) the Visual Analogue Scale (VAS) score within 24 hours.

Safety outcomes

• Incidences of angiographic complications during and within 24 hours after the procedure;
• Incidences of major angiographic complications during and within 24 hours after the procedure:
  • Access route associated complications (catheter kink or fracture, artery dissection, artery perforation, artery occlusion, compartment syndrome, arteriovenous fistula, retroperitoneal hematoma, hemorrhage, severe limb ischemia, embolism in any new territory, pseudoaneurysm, subcutaneous hematoma, and arterial spasm, etc.). Any complication which results in permanent sequelae, requires hospitalization, prolongation of existing hospitalization, any surgery or other medical intervention, or leads to death will be considered as a major complication, while all other complications will be considered as minor complications.
  • Neurological complications (cerebral infarction, intracranial hemorrhage, cortical blindness, nerve injury, nervous system infection, contrast encephalopathy, and vasovagal reactions including decreased blood pressure, decreased heart rate, cold sweat, pale, clammy limbs, etc.). Any complication which results in permanent sequelae, requires hospitalization, prolongation of existing hospitalization, any surgery or other medical intervention, or leads to death will be considered as a major complication, while all other complications will be considered as minor complications.

Data collection and management

Data will be entered into electronic case report forms (eCRFs) by clinical investigators and supporting trial personnel. An independent imaging core laboratory will determine the rate of successful diagnostic angiography and accurate diagnosis. The duration of angiography, fluoroscopy and bedridden time will be recorded by clinical investigators. The VAS score, assessed within 24 hours after the procedure, will be used to evaluate pain intensity. Any angiographic complications during and within 24 hours after the procedure will be recorded. To promote participant retention and complete follow-up, the investigators, doctors, and nurses will take very care of the participants in the trial until the scheduled last follow-up visits.

All data are stored in an electronic database via eCRFs. Only authorized clinical investigators and trial personnel will be granted access to the study database by a personal ID. All study-related documents, including consent forms and various data collection forms will be shredded and discarded 5 years after completion of this study.

All personal and medical data gathered will be encoded and documented according to the principles of good clinical practice. Sharing with anyone outside of the study team is strictly forbidden. Each participant will be assigned a unique study ID to ensure that data is stored anonymously. As previously outlined, the database is safeguarded with a password. Only the steering committee and the study team members when this is necessary in the interest of the trial will have access to the anonymized data.

DSMB

A DSMB was established, comprising a specialist in neuroscience and clinical medicine, a neurointerventional radiologist, and a biostatistician. The DSMB operates independently from the study sponsor and had no competing interests. The DSMB will routinely receive blinded statistical reports and oversee serious AEs (SAEs) throughout the trial. The DSMB is responsible for assessing patient safety and has the authority to recommend the premature closure of the trial if necessary.

Any AE or SAE observed in this clinical trial should be clearly documented in the “Adverse Events” section of the case report form. For individual AE: any AE resulting in death should be reported within 7 days; any AE that results in or may results in serious injury or death shall be reported through the China Medical Device Adverse Event Monitoring System within 20 days; for any medical device AE that occurs in a group of subjects: the event should be reported to the drug regulatory administration and health administration of the province, autonomous region or municipality directly under the Central Government within 12 hours by telephone or fax, and it may be reported to the authority of the higher level if necessary. At the same time, the basic information of the AE shall be reported through the National Medical Device Adverse Event Monitoring System. Each incident should also be reported within 24 hours on a case-by-case basis.

The Clinical Research Coordinator (CRC) will maintain regular communication with the investigators to ensure the integrity of all collected data and study procedures within this trial. The principal investigator will oversee data management, ensuring adherence to the protocol in both conduct and reporting. Additionally, the project management group will convene weekly to review trial conduct throughout the study period.

Sample size

This study will test the hypothesis that that the success rate of diagnostic cerebral angiography via TRA is not inferior to that via TFA. We assume the success rates of diagnostic cerebral angiography via TRA and TFA are 97% and 98% respectively by considering the data in the references, with a margin for non-inferiority of −5%, a power of 90% at one-side significance level of 0.025, and a drop-out rate of 10%, 429 cases are needed for each group according to PASS 15 software, and thus a total of 858 subjects need to be enrolled in this study.

Statistical analysis

Statistical methods for primary and secondary outcomes

The primary analysis is to evaluate the rate of successful diagnostic cerebral angiography and to assess the success rate of diagnostic cerebral angiography via TRA is not inferior to TFA. It will be analyzed based on Full Analysis Set (FAS) and Per Protocol Set (PPS), and FAS will be used as the main dataset for effectiveness analysis. The Clopper-Pearson method will be used to calculate the 95% confidence intervals (CIs) for rate of successful diagnosis in both groups, as well as the difference in rates between the two groups and its 95% CI (Miettinen-Nurminen method). Chi-squared tests will be used for non-inferiority tests for rates of successful diagnosis in both groups, and odds ratio (OR) with 95% CI between the two groups will be calculated by logistic regression model. A statistical description of rate of successful accurate diagnosis, duration of angiography, duration of fluoroscopy, bedridden time and VAS score will be provided, and the secondary efficacy outcomes will be analyzed using the linear mixed model with group as covariate and study center as random effect. In addition, logistic regression will be used to conduct an exploratory analysis of factors affecting cerebral angiography through TRA approach. Influencing factors may include age, diabetes, hypertension, hyperlipidemia, smoking history, Type III aortic arch configuration, looping technique, diameter and development status of the radial artery, development status of the aortic arch and arch vessels and degree of tortuosity, previous history of surgery on the radial artery.

The safety and efficacy interim analyses will be performed when randomization and 30-day follow-up are completed of 430 participants. Missing data will be avoided as possible by strengthening project management and improving data collection and organization. Missing data will not be imputed in this study.

Progress to data

The inclusion of participants started on 15 September, 2023. At a meeting of the DSMB on June 13, 2024, there were 541 subjects enrolled at 13 active sites in China. After reviewing data on a planned single interim analysis of 430 randomized participants, they recommended to continue the study as planned. All patient enrollments were completed on November 4, 2024.

Discussion

In cardiovascular angiography and interventions, multiple studies have established that TRA offers advantages over TFA, including reduced bleeding risks, faster patient recovery, increased comfort and lower incidence of access site complications. However, despite numerous retrospective studies highlighting the feasibility and safety of the TRA for cerebral angiography, it has not yet become the preferred method for cerebral angiography due to several obstacles, such as long learning curve, technical challenges and procedure complexity.

There is a notable learning curve associated with radial artery puncture due to the radial artery’s smaller size and its propensity for vasospasm, leading to a significantly lower success rate compared to femoral artery puncture (6,12). Furthermore, some anatomic features including a radial artery diameter <2 mm, radial artery loops, a tortuous brachiocephalic artery and an aberrant right subclavian artery make it more challenging to super-select secondary vessels on the aortic arch via TRA, resulting in a lower success rate compared to TFA (13,14). Therefore, studies have shown that the puncture time, procedural time, and fluoroscopy time for cerebral angiography using TFA are significantly shorter than those for TRA (15-17). However, with increasing surgical experience and advancements in technology, the procedural and fluoroscopy times for TRA have decreased substantially with the same success rate of diagnostic cerebral angiography. Experienced physician can even achieve shorter times with TRA than those achieved with the femoral approach (18). In addition, TRA also offers significant advantages for cerebral angiography in patients with type II–III aortic arches, bovine arches, or other vascular variations, greatly reducing procedural difficulty and decreasing both fluoroscopy and surgical times (19). TRA is also particularly effective for diagnosing and treating posterior circulation lesions compared to TFA (20). Therefore, TRA holds significant promise and value in cerebrovascular angiography.

Nevertheless, due to the lack of evidence-based evidence, TFA remains the preferred arterial approach for cerebral angiography and interventional treatments, with TRA often used as an alternative. Therefore, this project proposes a multicenter, randomized controlled study to compare the effectiveness and safety of TRA versus TFA in cerebral angiography and the implantation of hemodynamic guidance devices. This study aims to provide high-level, evidence-based insights into the application of TRA in neurointervention, potentially facilitating its broader adoption in cerebral angiography and interventional treatments.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the SPIRIT reporting checklist. Available at https://jni.amegroups.com/article/view/10.21037/jni-24-9/rc

Data Sharing Statement: Available at https://jni.amegroups.com/article/view/10.21037/jni-24-9/dss

Peer Review File: Available at https://jni.amegroups.com/article/view/10.21037/jni-24-9/prf

Funding: This study will be supported by Science and Technology Innovation Joint Foundation of Fujian Province (No. 2023Y9112).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jni.amegroups.com/article/view/10.21037/jni-24-9/coif). This article will be supported by Science and Technology Innovation Joint Foundation of Fujian Province (No. 2023Y9112). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics review committee of Huashan Hospital, Fudan University (No. 2023502) and ethics committee at each participating hospital. Informed consent will be obtained from all individual participants or their surrogates.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Dawkins AA, Evans AL, Wattam J, et al. Complications of cerebral angiography: a prospective analysis of 2,924 consecutive procedures. Neuroradiology 2007;49:753-9. [Crossref] [PubMed]
2. Bhat FA, Changal KH, Raina H, et al. Transradial versus transfemoral approach for coronary angiography and angioplasty - A prospective, randomized comparison. BMC Cardiovasc Disord 2017;17:23. [Crossref] [PubMed]
3. Campeau L. Percutaneous radial artery approach for coronary angiography. Cathet Cardiovasc Diagn 1989;16:3-7. [Crossref] [PubMed]
4. Jolly SS, Yusuf S, Cairns J, et al. Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial. Lancet 2011;377:1409-20. [Crossref] [PubMed]
5. Ge B, Wei Y. Comparison of Transfemoral Cerebral Angiography and Transradial Cerebral Angiography Following a Shift in Practice During Four Years at a Single Center in China. Med Sci Monit 2020;26:e921631. [PubMed]
6. Brunet MC, Chen SH, Peterson EC. Transradial access for neurointerventions: management of access challenges and complications. J Neurointerv Surg 2020;12:82-6. [Crossref] [PubMed]
7. Rentiya ZS, Kuhn AL, Hutnik R, et al. Transradial access for cerebral angiography and neurointerventional procedures: A meta-analysis and systematic review. Interv Neuroradiol 2024;30:404-11. [Crossref] [PubMed]
8. Snelling BM, Sur S, Shah SS, et al. Transradial cerebral angiography: techniques and outcomes. J Neurointerv Surg 2018;10:874-81. [Crossref] [PubMed]
9. Wang Z, Xia J, Wang W, et al. Transradial versus transfemoral approach for cerebral angiography: A prospective comparison. J Interv Med 2019;2:31-4. [Crossref] [PubMed]
10. Stone JG, Zussman BM, Tonetti DA, et al. Transradial versus transfemoral approaches for diagnostic cerebral angiography: a prospective, single-center, non-inferiority comparative effectiveness study. J Neurointerv Surg 2020;12:993-8. [Crossref] [PubMed]
11. Carraro do Nascimento V, de Villiers L, Dhillon PS, et al. Transradial versus transfemoral access for diagnostic cerebral angiography: frequency of acute MRI findings in 500 consecutive patients at a single center. J Neurointerv Surg 2025;17:181-5. [Crossref] [PubMed]
12. Chen SH, Brunet MC, Sur S, et al. Feasibility of repeat transradial access for neuroendovascular procedures. J Neurointerv Surg 2020;12:431-4. [Crossref] [PubMed]
13. Goldman DT, Bageac D, Mills A, et al. Transradial Approach for Neuroendovascular Procedures: A Single-Center Review of Safety and Feasibility. AJNR Am J Neuroradiol 2021;42:313-8. [Crossref] [PubMed]
14. Narsinh KH, Mirza MH, Duvvuri M, et al. Radial artery access anatomy: considerations for neuroendovascular procedures. J Neurointerv Surg 2021;13:1139-44. [Crossref] [PubMed]
15. Liu Y, Wen X, Bai J, et al. A Single-Center, Randomized, Controlled Comparison of the Transradial vs Transfemoral Approach for Cerebral Angiography: A Learning Curve Analysis. J Endovasc Ther 2019;26:717-24. [Crossref] [PubMed]
16. Kenawy AE, Tekle W, Hassan AE. Improved Fluoroscopy and Time Efficiency with Radial Access for Diagnostic Cerebral Angiography. J Neuroimaging 2021;31:67-70. [Crossref] [PubMed]
17. Bhatia K, Guest W, Lee H, et al. Radial vs. Femoral Artery Access for Procedural Success in Diagnostic Cerebral Angiography : A Randomized Clinical Trial. Clin Neuroradiol 2021;31:1083-91. [Crossref] [PubMed]
18. Wilkinson DA, Majmundar N, Catapano JS, et al. Transradial cerebral angiography becomes more efficient than transfemoral angiography: lessons from 500 consecutive angiograms. J Neurointerv Surg 2022;14:397-402. [Crossref] [PubMed]
19. Snelling BM, Sur S, Shah SS, et al. Unfavorable Vascular Anatomy Is Associated with Increased Revascularization Time and Worse Outcome in Anterior Circulation Thrombectomy. World Neurosurg 2018;120:e976-83. [Crossref] [PubMed]
20. Maud A, Khatri R, Chaudhry MRA, et al. Transradial Access Results in Faster Skin Puncture to Reperfusion Time than Transfemoral Access in Posterior Circulation Mechanical Thrombectomy. J Vasc Interv Neurol 2019;10:53-7. [PubMed]