Therapeutic strategies in vascular cognitive impairment: A systematic review and meta-analysis.

INTRODUCTION: Vascular cognitive impairment (VCI) is a common, heterogeneous condition, currently lacking approved treatments. METHODS: We reviewed therapeutic strategies tested in VCI and meta-analyzed efficacy data for eligible interventions to assess whether previously tested treatments warranted reconsideration. RESULTS: One-hundred seventy-three trials were extracted (22,347 participants, four VCI categories, 91 interventions, 145 outcomes). Ginkgo biloba extracts showed large to moderate improvements in cognition (Cohen's d: 0.83, 95% CI: 0.00 to 1.67) and small to moderate improvements in functional outcomes (Cohen's d: 0.50, 95% CI: 0.25 to 0.75). Small to moderate improvements in cognition were shown for acetylcholinesterase inhibitors, memantine, cerebrolysin, propentofylline, physical exercise, and cognitive rehabilitation. DISCUSSION: VCI clinical trials exhibited substantial heterogeneity. Few interventions were reproducibly tested in adequately sized and designed studies. Nonetheless, some interventions showed modest effects on global cognition and functional outcomes. To enhance the likelihood of success, future studies should focus on promising interventions with a solid rationale, target specific VCI subtypes, improve statistical power, and reduce heterogeneity. HIGHLIGHTS: Considerable methodological heterogeneity across VCI trials undermined the strength of evidence for both positive and negative findings, ultimately decreasing confidence in the possibility of treating VCI. Ginkgo biloba extracts have shown the greatest cognitive and functional benefits, though their clinical significance remains uncertain, and certainty of evidence is overall low. Future trials should focus on a single VCI subtype, prioritize interventions with a strong mechanistic rationale, standardize diagnostic criteria, ensure adequate power for chosen outcomes, test against placebo, and implement FAIR data sharing to accelerate therapeutic discovery.