Hemoglobin as a predictor of functional outcome

Our analysis found a statistically significant association between greater Hb and positive functional outcomes at three months, according to the mRS score. More specifically, the pooled OR revealed that for every 1 g/dL increase in Hb, the odds of achieving an excellent functional outcome (mRS 0–2) improved by 22%. These findings are consistent with the results of earlier observational studies that found anemia to be a poor prognostic indicator in AIS.^{Reference Kellert, Martin and Sykora22,Reference Milionis, Papavasileiou, Eskandari, D’Ambrogio-Remillard, Ntaios and Michel23}

The underlying pathophysiological reason for this relationship is the importance of Hb for oxygen delivery. In patients with AIS, vascular occlusion will reduce cerebral blood flow and create a mismatch between oxygen delivery and consumption.^{Reference Li, Zhou, Li, Chen and Chen24} The ischemic penumbra (hypoperfused but viable cerebral tissue) is of particular concern in developing hypoxia. In animal models, sufficient Hb in the bloodstream was critical to sustaining oxygen in the penumbra and supporting neuronal metabolic needs for repair and recovery after reperfusion.^{Reference Gao, Peng, Yang, Li and Xiang25,Reference Gekka, Abumiya and Komatsu26} However, this suggested pathophysiological mechanism should be approached with caution. Pensato and colleagues^{Reference Pensato, Bosshart and Stebner27} demonstrated that anemia is not associated with a significant change in ischemic core volume, which might suggest that anemia is a bystander in the worse prognosis among those patients. In this regard, the etiology of anemia, which is expected to vary in this population of patients, might be the main factor influencing the EVT outcomes, not the anemia itself. For instance, anemia of chronic inflammation is mediated by certain inflammatory cytokines such as interleukin 6 and tumor necrosis factor alpha.,^{Reference Agarwal and Prchal28,Reference Means29} which are known to be associated with worse stroke outcomes.^{Reference Castellanos, Castillo and Garcia30,Reference Pawluk, Grzesk and Kolodziejska31}

On the other hand, the potential risks of a very high Hb level must be simultaneously addressed. Our analysis suggests better outcomes occur with higher Hb levels, but elevated Hb can increase blood viscosity and raise the risk of thromboembolic adverse events.^{Reference Hultcrantz, Modlitba and Vasan32} However, the optimal Hb target in AIS patients still needs to be determined.

Hemoglobin as a predictor of mortality

Our findings also demonstrate the association of low Hb levels with increased mortality at three months post-EVT. Specifically, patients with Hb ≤13 g/dL (in males) or ≤12 g/dL (in females) had a higher risk of dying within three months than patients with higher Hb levels. Patients with Hb <10 g/dL were also at a higher risk of mortality than those with higher Hb levels, which highlights the importance of having adequate Hb values in this patient population.

These observations are consistent with other recent studies assessing anemia as a predictor of poor outcomes among critically ill patients.^{Reference Lee, Kini, Ahsan, Fisher and Sharma33,Reference Sico, Concato and Wells34} The presence of anemia can worsen cerebral hypoxia by decreasing the capacity of the blood to deliver sufficient oxygen to the cerebral tissue, especially in the ischemic region.^{Reference Tsai, Yip, Chen, Yeh, Chung and Jeng35} Anemia may also serve as an indirect marker of some overall physiological frailty and inherent comorbidities, such as chronic kidney disease or malignancy, which potentially leads to poor outcomes after an AIS. It should be considered whether correcting anemia aggressively among AIS patients, primarily with transfusion strategies, would improve survival outcomes.

Nonetheless, the utility of blood transfusion in stroke patients is a topic of controversy. Transfusion may improve oxygen delivery, but it may also increase the risk of complications like infection and thromboembolism.^{Reference Marik36,Reference Whitson, Huddleston, Savik and Shumway37}

Symptomatic intracranial hemorrhage (sICH)

In contrast to its significant association with mortality and functional outcomes, our meta-analysis did not observe a significant association between Hb levels and sICH risk. This finding is crucial in many respects since anemia has also been associated with an increased risk of hemorrhagic transformation in patients with AIS, particularly among those receiving reperfusion therapy.^{Reference Iancu, Buleu, Chita, Tutelca, Tudor and Brad38,Reference Wang, Wang and Zhong39} One possible explanation for this discrepancy is the limited sample size within our analysis. Additionally, other factors, such as the use of anticoagulation, the stroke’s severity or the reperfusion’s success, may have significantly influenced the risk of sICH compared to Hb levels alone.

While our findings showed no apparent association, the risk of sICH should still be considered when caring for AIS patients undergoing EVT. EVT has associated reperfusion injury risk, which could lead to hemorrhagic transformation, particularly in patients with large infarcts or prolonged ischemia.^{Reference Baracchini, Farina and Palmieri40,Reference Katsanos, Srivastava and Sahlas41}

Clinical implications

The results of this study have a range of clinical implications. First, Hb levels should be routinely assessed in AIS patients with EVT since they may represent a valuable prognostic biomarker of functional recovery and survival. Identifying patients with critically low Hb levels might allow for a better understanding of the clinical outcomes. With a deeper understanding in this regard, future directions in clinical research might aim to investigate if corrective interventions for significant anemia in AIS-LVO patients will improve the clinical outcomes after EVT.

Second, we provide evidence of a threshold effect since lower Hb levels are associated with significantly poorer outcomes. Thus, we predict that clinicians should aim to normalize Hb levels before EVT in patients with a previous history of anemia to limit the risk of worsened outcomes in those patients. However, one must consider the consequences of excessive blood correction, such as increased blood viscosity and thromboembolism.

Strengths and limitations

To the best of our knowledge, this is the largest meta-analysis examining the potential effects of Hb level variations on the clinical and procedural outcomes of EVT for AIS-LVO. However, some limitations in this meta-analysis should be acknowledged. First, the limited number of studies might limit generalizability. Second, while observation studies were included, this introduced the risk of residual confounding. While we attempted to control for confounders through pooled ORs and RR, residual confounding through unmeasured factors (stroke severity, comorbid conditions) must still be considered a limitation.

Third, the need for standardized Hb thresholds across studies complicates the interpretation of our results. Studies have used differing cut-off values to define anemia, which may have influenced the strength of associations noted in our findings. Additionally, there is a lack of data in the included studies on the timepoints at which the Hb level was determined: before versus immediately after the EVT procedure. Moreover, we were not able to conduct a subgroup analysis in patients with low Hb levels according to comorbid conditions that might be significant confounders of the Hb level’s impact on EVT outcomes. Finally, these results might, in turn, be susceptible to publication bias. A formal assessment of publication bias could not be done due to the few studies included.