SAHaRA Trial
Aneurysmal SubArachnoid Hemorrhage - Red Blood Cell Transfusion And Outcome (SAHaRA): A Randomized Controlled Trial 

Background: 
Aneurysmal subarachnoid hemorrhage (aSAH) is an important disease with devastating outcomes. Morbidity can be profound, with less than one third of survivors achieving a full functional recovery. Anemia is common in these patients and is a potential critical factor affecting secondary injury, an often protracted process. Despite physiologic evidence and management guidelines that support maintaining a higher hemoglobin level in patients with aSAH, current stated practice from surveys and from our multi-center cohort study suggests a more restrictive approach to transfusion in a similar fashion to other critical care patients. The clinical importance of varied transfusion thresholds in aSAH has never been studied in a large and rigorous randomized trial. In our internal pilot RCT we have demonstrated the feasibility of patient enrolment and trial conduct. In collaboration with the Canadian Critical Care Trials Group, we aim to conduct an open-label single blind RCT in adult patients with aSAH to examine the effect of a liberal compared to restrictive RBC transfusion strategy (Hb trigger ≤100g/L vs ≤80g/L respectively) on 12 month functional neurologic outcome.

Objectives:  
Primary: To determine if a liberal compared to restrictive RBC transfusion strategy (Hb trigger ≤100g/L vs ≤80g/L respectively) in adult patients suffering from acute aSAH and anemia (Hb≤100g/L) decreases the combined rate of death and severe disability at 12 months.
Secondary: To evaluate the effect of a liberal versus a restrictive (Hb trigger ≤100g/L vs ≤80g/L) RBC transfusion strategy in acute aSAH patients with anemia (Hb≤100g/L) on: a) 12-month overall function and quality of life; b) mortality and c) delayed cerebral infarcts on routine follow-up CT scans.

Methods:  
Design/Setting: Multicentre pragmatic, open-label blinded-endpoint randomized control trial. 
Participants: Adult aSAH patients within 10 days of their initial bleed and anemia (Hb of ≤ 100 g/L) will be eligible for enrolment. 
Randomization: Web-based central computer-generated randomization, stratified by centre, will be undertaken from the host centre. 
Intervention: Patients will be randomly assigned to either a liberal (Hb≤100g/L) or a restrictive (Hb≤80g/L) transfusion trigger strategy for the first 21 days. 

Outcome: 
Primary: 12 month modified Rankin Scale score. 
Secondary: a) Functional Independence Measure (FIM) and the EuroQOL Quality of Life Scale (EQ5D) at 12 months, b) number of RBC units transfused, c) lowest daily hemoglobin, d) transfusion-related complications, e) incidence and severity of delayed cerebral ischemia and vasospasm, f) incidence of cerebral infarction, g) need for and duration of mechanical ventilation, h) ICU and hospital lengths of stay, and i) mortality. 

Sample Size: 
To demonstrate a 10% absolute reduction (40% to 30%, 25% relative improvement) in our primary outcome in the intervention group, a sample size of 740 patients is necessary assuming 80% power, a type I error of 5% and a conservative 3% adjustment for loss to follow-up. 

Analysis: 
Our primary outcome will be examined by Mantel-Haenszel chi-square statistics and presented as the absolute risk reduction.

Significance: 
The SAHaRA trial will clarify the role of treating anemia with RBC transfusion in this unique and vulnerable patient population, and determine whether that impacts on functional outcomes and mortality. It will guide best practice standards and clarify the optimal RBC transfusion strategy in patients with aSAH.

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