Emergent aneurysm treatment compared with treatment on neurological improvement in patients with ruptured poor-grade aneurysmal subarachnoid haemorrhage: the TOPSAT2 RCT
Authors: White Philip , Gregson Barbara , McColl Elaine , Brennan Paul , Steel Alison , Watts Philippa , Wood Ruth , Bowes Clare , Javadpour Mohsen , Weston Amanda , Mitra Dipayan 
Published: July 2021

Background
Aneurysmal subarachnoid haemorrhage is a major cause of haemorrhagic stroke. The incidence is ≈ 80 per million population per year; it peaks in the 40–60 years age range and often has a poor prognosis with the outcome linked to severity of the initial haemorrhage. Aneurysmal subarachnoid haemorrhage accounts for 5% of strokes, but 20% of quality-adjusted life-years are lost to stroke and much of that loss is concentrated in World Federation of Neurosurgical Societies grade 4–5 (or poor-grade) aneurysmal subarachnoid haemorrhage patients. Before endovascular coiling was available, the conventional management strategy for poor-grade aneurysmal subarachnoid haemorrhage patients was to treat the ruptured aneurysm on neurological improvement. That incurs a risk of aneurysm rebleeding, which is highest soon after the first bleed; if rebleed occurs prior to aneurysm treatment, prognosis is dismal. Reducing rebleeding with early treatment might improve outcome. Therefore, an early coiling strategy in grade 4–5 patients is appealing, but not robustly evidenced. Early treatment in all grade 4–5 patients might prevent death from rebleeding but possibly at the expense of creating severely disabled survivors, with attendant societal costs. Many neuroclinicians have expressed genuine uncertainty regarding whether or not to treat all grade 4–5 aneurysmal subarachnoid haemorrhage patients emergently (as soon as possible regardless of neurological status). A pilot trial, the treatment of poor-grade subarachnoid haemorrhage trial 1 (TOPSAT1), indicated that recruitment to a randomised trial to address this uncertainty was feasible.

Methods
We investigated a management policy in aneurysmal subarachnoid haemorrhage World Federation of Neurosurgical Societies grades 4 or 5 of securing the ruptured aneurysm emergently (within 24 hours of randomisation) compared with the strategy to treat the aneurysm on neurological improvement (to World Federation of Neurosurgical Societies grades 1–3), irrespective of when that improvement occurred. The treatment of poor-grade subarachnoid haemorrhage trial 2 (TOPSAT2) was a pragmatic, randomised, open-blinded, end-point design trial aiming to recruit 346 adult patients (aged 18–80 years) in 30 UK and European neuroscience centres. Randomisation was web based, with minimisation criteria relating to age, grade, presence of hydrocephalus and UK location (vs. non-UK). Fifteen sites were opened to recruitment, 12 of which were in the UK. Standard institutional procedures for securing aneurysms were followed. An exploratory magnetic resonance biomarker substudy of 100 UK participants was planned but not opened. The primary end point was functional outcome at 12 months, determined by analysis of the modified Rankin Scale score. The secondary end points relating to safety were assessed.

Results
Of the 305 World Federation of Neurosurgical Societies grade 4–5 patients screened, 23 were randomised: 11 to the emergent treatment arm and 12 to the treatment on neurological improvement (control) arm. Trial recruitment was suspended when it was judged to have failed a feasibility assessment. The median time from ictus to treatment (where aneurysm was treated) was 26 hours in the emergent treatment arm and 163 hours in the treatment on neurological improvement arm. There were no statistically significant differences between arms in mortality (p = 0.4) or functional outcome at 365 days [modified Rankin Scale score 0–3 vs. 4–6 (p = 0.32)]. Sensitivity analysis was performed to examine the effect of missing data but differences remained non-significant.

Limitations
A limitation was the failure to recruit to time/target.

Conclusions
The randomised trial approach to investigating whether poor-grade aneurysmal subarachnoid haemorrhage patients should receive emergent treatment or be treated on neurological improvement proved unfeasible. No statistically significant differences were identified between the trial arms in mortality or functional outcome, but the small number of patients enrolled limits drawing firm conclusions.

Future work
No future work is currently planned.

Trial registration
Current Controlled Trials ISRCTN15960635.

Funding
This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 8. See the NIHR Journals Library website for further project information.