Cytoflavin's neuroprotective effect in acute ischemic stroke: a systematic review and meta-analysis

Acute ischemic stroke (AIS) remains a leading cause of long-term disability globally. While reperfusion therapies are effective, there is a growing need for adjunct neuroprotective strategies to minimize secondary brain injury. Cytoflavin, a metabolic and antioxidant compound, has shown potential neuroprotective effects. However, its clinical efficacy remains underexplored. This systematic review and meta-analysis aim to evaluate the efficacy of Cytoflavin in AIS, focusing on neurological recovery (NIHSS), functional independence (Barthel Index), cognitive performance (MMSE), and infarct volume. A systematic search was conducted across multiple databases for studies evaluating Cytoflavin in AIS. Nine studies were included, with a combined enrollment of 3,254 participants across treatment arms (sample sizes reported per arm); the number of unique participants contributing to each pooled outcome was smaller after correcting for shared control groups and repeated-measures overlap across evaluation time points (e.g., 1,379 for NIHSS). Data were analyzed using random-effects models; where a shared control group was compared against two Cytoflavin dose arms within the same study, the control group was split proportionally between the two comparisons to avoid double-counting participants (unit-of-analysis correction). Risk of bias was assessed using Cochrane Risk of Bias tool and Newcastle-Ottawa Scale. Cytoflavin significantly improved NIHSS scores (MD = −2.63, 95% CI: −3.15 to −2.10; moderate certainty) and Barthel Index (MD = 19.29, 95% CI: 9.52 to 29.07; moderate certainty), and showed improvements of low certainty in MMSE scores (MD = +6.93, 95% CI: 1.39 to 12.47) and mRS scores (MD = −0.41, 95% CI: −0.74 to −0.09), the latter derived from continuous summary statistics for an inherently ordinal scale (see Limitations). For infarct volume, effects diverged by evaluation time point: a marginal increase was observed at Day-10 (MD = +0.17 cm 3 , based on a single study), while a non-significant reduction was observed at Day-21 (MD = −4.73 cm 3 , 95% CI: −11.41 to 1.95; very low certainty). High heterogeneity (I 2 ranging from 0% to 100%) was observed across outcomes and persisted after the unit-of-analysis correction, indicating genuine clinical and methodological diversity across studies. In conclusion, cytoflavin shows promising neuroprotective effects in AIS. However, due to heterogeneity and methodological limitations, further large-scale, high-quality studies are needed to confirm its efficacy and optimize treatment protocols. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251112430 , identifier: CRD420251112430.