International Subarachnoid Aneurysm Trial II

Intracranial Hemorrhage Ruptured Aneurysm Clinical Trial

— ISAT II  

Official title:

International Subarachnoid Aneurysm Trial II Comparing Clinical Outcomes of Surgical Clipping and Endovascular Coiling for Ruptured Intracranial Aneurysms Not Included in the Original ISAT Study.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01668563
• Other study ID #: CE 12.136
• Status: Recruiting
• Phase: N/A
• Start date: November 12, 2012
• Est. completion date: June 2024

Study information

• Verified date: July 2023
• Source: Centre hospitalier de l'Université de Montréal (CHUM)
• Contact: Roland Jabre, MD
• Phone: 514-890-8000
• Email: roland.jabre.med[@]ssss.gouv.qc.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to compare the clinical outcome of surgical clipping and endovascular coiling for ruptured intracranial aneurysms not included in the original ISAT Study.

Description:

The International Subarachnoid Aneurysm Trial (ISAT) was a turning point in modern neurosurgical history (1). The trial showed that for 2143 subarachnoid hemorrhage (SAH)patients eligible for both surgery and endovascular coiling, randomized allocation to coiling was associated with better one year clinical outcomes, defined as survival without dependency (absolute risk reduction (ARR) of 7.4% (95%CI; 3.6 - 11.2, p=0.0001). Because ISAT was a positive pragmatic trial, the interpretation of the trial results was that coiling should be adopted as the first-line treatment for ruptured lesions, for patients with the types of aneurysms included in ISAT, of which the great majority were small (≥10 mm) anterior circulation aneurysms.

Although ISAT was well-designed, conducted, and reported, trial results were not always properly interpreted, and endovascular coiling was perhaps inappropriately extrapolated beyond what ISAT demonstrated. Endovascular treatment for ruptured aneurysms has now become first-line treatment in many centers (2), which may be appropriate for small, anterior circulation lesions, but there is no evidence to support this practice for the wide spectrum of non-ISAT patients and aneurysms. A recent pre-randomized study of coiling as first-intention (3)showed better results for those ruptured aneurysms felt to be readily coilable; however, the optimal management of more difficult-to-coil ruptured aneurysms remains unclear.

Further compounding the problem are the concerns that aneurysm coiling may not be as durable in the long-term as surgical clipping, leading many neurosurgeons to continue to clip most ruptured aneurysms in spite of ISAT results.

Proponents of endovascular treatment sometimes justify this extrapolation of ISAT results on the basis of improved catheter and coil technology, although this has never been demonstrated. However, the addition of stents and flow-diverters, which were not tested in ISAT, may increase endovascular treatment risks, especially when combined with dual anti-platelet agents. The introduction of these devices allowed for the expansion of indications of EVT to include wide-necked aneurysms, lesions which would not have been included in ISAT. The wider spectrum of patients and aneurysms now considered for EVT may not all experience the same degree of benefit as seen in the original ISAT trial (4). Considering the relatively small ARR of 7.4% favouring coiling, when the additional risks due to stents are included, the balance may have tipped to favour surgical clipping.

These new questions deserve formal study in the context of a randomized clinical trial.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1724
• Est. completion date: June 2024
• Est. primary completion date: December 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients at least 18 years of age

• At least one documented, intradural, intracranial aneurysm, ruptured within last 30 days

• SAH WFNS grade 4 or less

• The patient and aneurysm are considered appropriate for either surgical or endovascular treatment by the treating team

Exclusion Criteria:

• Patients with absolute contraindications administration of contrast material (any type)

• Patients with AVM-associated aneurysms

• Aneurysm located at basilar apex

Related Conditions & MeSH terms

• Aneurysm
• Aneurysm, Ruptured
• Hemorrhage
• Intracranial Aneurysm
• Intracranial Hemorrhage Ruptured Aneurysm
• Intracranial Hemorrhages

Intervention

Procedure:
• surgical management
Surgical clipping will be performed as soon as possible following randomization, according to standards of practice, and under general anesthesia. Aneurysms thought by the treating physicians to require deliberate permanent proximal vessel occlusion, construction of a surgical bypass, or other flow-redirecting treatments that do not directly clip the aneurysm will not be excluded; these non-ISAT aneurysms are expected to be more difficult lesions to manage surgically as well as endovascularly.
• Endovascular management
Endovascular treatment will also be performed as soon as possible following randomization,according to standards of practice, and under general anesthesia. Details regarding type of coils, use of adjunctive techniques such as balloon-remodeling, stents or flow-diverters, as well as post-treatment medical management issues, will be left up to the physician performing the endovascular treatment.

Locations

Country	Name	City	State
Canada	Foothills Medical Centre	Calgary	Alberta
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	Centre Hospitalier de l'Université de Montréal - Hôpital Notre Dame	Montreal	Quebec
Spain	Vall d'Hebron Hospital	Barcelona
Spain	University of Valladolid	Valladolid
United States	Montefiore Medical Center	Bronx	New York

Sponsors (1)

Lead Sponsor	Collaborator
Centre hospitalier de l'Université de Montréal (CHUM)

Countries where clinical trial is conducted

United States,  Canada,  Spain, 

References & Publications (4)

Gnanalingham KK, Apostolopoulos V, Barazi S, O'Neill K. The impact of the international subarachnoid aneurysm trial (ISAT) on the management of aneurysmal subarachnoid haemorrhage in a neurosurgical unit in the UK. Clin Neurol Neurosurg. 2006 Feb;108(2):117-23. doi: 10.1016/j.clineuro.2005.11.001. Epub 2005 Dec 20. — View Citation

McDougall CG, Spetzler RF, Zabramski JM, Partovi S, Hills NK, Nakaji P, Albuquerque FC. The Barrow Ruptured Aneurysm Trial. J Neurosurg. 2012 Jan;116(1):135-44. doi: 10.3171/2011.8.JNS101767. Epub 2011 Nov 4. — View Citation

Molyneux A, Kerr R, Stratton I, Sandercock P, Clarke M, Shrimpton J, Holman R; International Subarachnoid Aneurysm Trial (ISAT) Collaborative Group. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet. 2002 Oct 26;360(9342):1267-74. doi: 10.1016/s0140-6736(02)11314-6. — View Citation

Raymond J, Kotowski M, Darsaut TE, Molyneux AJ, Kerr RS. Ruptured aneurysms and the International Subarachnoid Aneurysm Trial (ISAT): What is known and what remains to be questioned. Neurochirurgie. 2012 Apr-Jun;58(2-3):103-14. doi: 10.1016/j.neuchi.2012.02.020. Epub 2012 Apr 4. English, French. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	poor clinical outcome(mRS>2)	Number of patients experiencing a poor clinical outcome at one year post-treatment, defined as a modified Rankin Scale (mRS) score of >2.	12 months
Secondary	Occurrence of an intracranial hemorrhage following treatment	An intracranial hemorrhage will be judged from cross-sectional imaging (CT or MRI), from a positive lumbar puncture in the setting of an acute headache, or following sudden death preceded by an acute headache.	one year
Secondary	Failure of aneurysm occlusion using the intended treatment modality	In situations where treatment is initiated but terminated without a proper test of that treatment modality, such as in the event of anaesthetic difficulty requiring the intended treatment to be delayed, will not count as a failure. However, patients left with clinically concerning aneurysm residuals (in the opinion of the treating physician) after the treatment attempt will count as a failure of the initial treatment.	within 48 hours after attempted treatment
Secondary	Overall mortality and morbidity	Mortality and morbidity from all causes will be recorded, along with cause of death, at one and five years.	one year and five years
Secondary	Occurence of a "major" (saccular) aneurysm recurrence	Determined using non-invasive angiography (CTA or MRA)as part of normal follow-up after aneurysm treatment. Although DSA, CTA and MRA are known to have different sensitivities in detecting aneurysm remnants,these modalities are equally well-suited to the discovery of a concerning, saccular aneurysm residual or remnant.	12 months (+/- 2 months)
Secondary	Peri-treatment hospitalization lasting more than 20 days and/or discharge to a location other than home	Will be recorded by the local treating physician upon discharge.	within a month or at discharge if earlier
Secondary	Occurence of aneurysm re-rupture following randomization but before treatment initiation	Repeat intracranial hemorrhage will be judged from cross-sectional imaging (CT scan), after worsening of headache, or following a new-onset neurological deficit or sudden death while awaiting treatment.	Within a few hours (while awaiting treatment)