Original Article: English SW, et al. Liberal or Restrictive Transfusion Strategy in Aneurysmal Subarachnoid Hemorrhage: SAHARA. N Engl J Med. 2025;392(11):1079–1088.

Background/Methods
Anemia frequently develops after aneurysmal subarachnoid hemorrhage (aSAH) and is linked to worse outcomes. While red blood cell (RBC) transfusions may improve oxygen delivery, they also pose risks such as thromboembolism and infection. Though ICU trials generally support restrictive transfusion strategies, their applicability to aSAH is unclear.

The SAHARA trial was a multicenter, pragmatic, open-label randomized trial conducted at 23 neurocritical care centers in the US, Canada, and Australia. Adults with a first-ever aSAH and hemoglobin (Hgb) ≤10 g/dL within 10 days of admission were randomized 1:1 to a liberal (transfuse if Hgb ≤10 g/dL) or restrictive (transfuse if Hgb ≤8 g/dL) strategy. Transfusions used leukodepleted RBCs, one unit at a time. The strategy was maintained for 21 days, until discharge or death. The primary outcome was unfavorable neurological outcome at 12 months (modified Rankin Scale [mRS] 4–6). Secondary outcomes included mortality, functional independence measure (FIM), and quality of life (EQ-5D-5L, visual analog scale). Outcome assessors were blinded.

Results
A total of 742 patients were enrolled: 364 to liberal transfusion and 361 to restrictive transfusion. The median time to randomization was 2.1 days, with balanced baseline characteristics. The primary outcome occurred in 33.5% of the liberal group vs. 37.7% of the restrictive group (RR 0.88; 95% CI, 0.72–1.09; p=0.22)—a nonsignificant difference.

Secondary outcomes were similar across groups. FIM scores and quality of life measures showed no significant differences. Mortality at 12 months was nearly identical: 27.2% (liberal) vs. 27.1% (restrictive). Radiographic vasospasm was lower in the liberal arm (31.5% vs. 40.7%), though this did not translate to reduced delayed cerebral ischemia (DCI) or infarction.

The liberal group received more RBC units (median 2 vs. 0), without an increase in adverse events such as thrombosis or infection. Protocol adherence was high, with few violations.

Commentary
SAHARA is the most robust trial to date evaluating transfusion thresholds in aSAH. The findings supported comparable safety between liberal and restrictive transfusion strategies, with no compromise in long-term outcomes between the two. Although the liberal group showed a modest numeric benefit in the primary outcome and rates of vasospasm, these were not statistically significant and did not translate into improved survival or function.

The lower vasospasm rate in the liberal group raises questions about potential physiologic effects of higher hemoglobin levels on cerebral oxygenation and autoregulation. However, vasospasm alone may not adequately predict clinical outcomes, a view increasingly reflected in recent literature.

Strengths of the study include its large sample size, international scope, blinded outcome assessment, and strong protocol fidelity. Limitations include modest hemoglobin separation between groups and underrepresentation of high-grade aSAH, which may limit generalizability. The open-label design also introduces the potential for treatment bias, though this was somewhat mitigated by blinded outcome assessment.

Overall, SAHARA suggests that outcomes in patients with aSAH may be comparable between liberal and restrictive transfusion strategies. Additional data from the recently published TRAIN trial exploring transfusion goals in patients with acute brain injury, a liberal transfusion strategy targeting a hemoglobin level of 9 g/dL was associated with fewer unfavorable neurological outcomes at 6 months. However, the acute brain injury population in TRAIN included patients with intracerebral hemorrhage and traumatic brain injury, in addition to subarachnoid hemorrhage. The HEMOTION trial, which exclusively enrolled traumatic brain injury patients, also evaluated liberal (hemoglobin <10 g/dL) versus restrictive (hemoglobin <7 g/dL) transfusion thresholds, finding no significant difference in outcomes at 6 months. The release of TRAIN has influenced a shift toward more liberal hemoglobin transfusion targets, at least during the delayed cerebral ischemia phase. Future research should focus on individualized transfusion thresholds during high-risk periods such as vasospasm, potentially guided by cerebral oxygenation or metabolic markers.