Clinical trial NCT01668563: International Subarachnoid Aneurysm Trial 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.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Intracranial Hemorrhage Ruptured Aneurysm
Keywords: Aneurysm
Intracranial Aneurysm
Vascular Diseases
Cardiovascular Diseases
Intracranial Arterial Diseases
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Lead sponsor: Centre hospitalier de l'Université de Montréal (CHUM)
Sponsor class: OTHER
First posted: 2012-08-20
Enrollment: 1724
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: poor clinical outcome(mRS>2)
timeFrame: 12 months
Secondary outcomes:
measure: Occurrence of an intracranial hemorrhage following treatment
timeFrame: one year
measure: Failure of aneurysm occlusion using the intended treatment modality
timeFrame: within 48 hours after attempted treatment
measure: Overall mortality and morbidity
timeFrame: one year and five years
measure: Occurence of a "major" (saccular) aneurysm recurrence
timeFrame: 12 months (+/- 2 months)
measure: Peri-treatment hospitalization lasting more than 20 days and/or discharge to a location other than home
timeFrame: within a month or at discharge if earlier
measure: Occurence of aneurysm re-rupture following randomization but before treatment initiation
timeFrame: Within a few hours (while awaiting treatment)
Other outcomes:
Locations:
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Calgary
country: Canada
facility: Foothills Medical Centre
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Montreal
country: Canada
facility: Centre Hospitalier de l'Université de Montréal - Hôpital Notre Dame
state: Quebec
city: Barcelona
country: Spain
facility: Vall d'Hebron Hospital
city: Valladolid
country: Spain
facility: University of Valladolid
Study officials:
affiliation: University of Alberta
name: Tim Darsaut, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alberta
name: Max Findlay, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: 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.
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.
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.
citation: Darsaut TE, Jack AS, Kerr RS, Raymond J. International Subarachnoid Aneurysm Trial - ISAT part II: study protocol for a randomized controlled trial. Trials. 2013 May 29;14:156. doi: 10.1186/1745-6215-14-156.