Systematic reviews and meta-analyses are essential tools in medical research. Systematic reviews are a type of literature review that uses a systematic process to identify and assess all available literature on a specific research question. A meta-analysis is a statistical method of synthesizing the results of a systematic review by quantitatively combining data. The process begins with formulating a well-defined research question using frameworks. Comprehensive literature searches across multiple databases, including PubMed, Embase, and Cochrane, to ensure the inclusion of diverse studies. Tools like EndNote and Covidence streamline reference management and study selection, enhancing efficiency and accuracy. Quality assessment using tools like the Cochrane Risk of Bias Tool and Newcastle-Ottawa Scale is crucial to evaluate the methodological rigor. Data extraction, using standardized forms to ensure consistent information capture. Qualitative synthesis is one method that integrates the results of a systematic review focusing on textual data. Meta-analysis employs statistical software such as R and RevMan to compute effect sizes, confidence intervals, and assess heterogeneity. Visual representations, including forest and funnel plots, facilitate the interpretation of results. Challenges such as publication bias and heterogeneity are addressed using statistical methods like Egger regression and the trim-and-fill technique. Sensitivity analyses further validate the robustness of findings. Common errors, including data entry mistakes and inappropriate pooling, are mitigated through rigorous methodological adherence and critical self-evaluation. Meticulously conducted, systematic reviews and meta-analyses represent the pinnacle of the evidence hierarchy, driving advancements in medical research and practice.

Cardiovascular disease (CVD) remains the leading global cause of death, with a growing interest in modifiable risk factors such as homocysteine. Elevated homocysteine contributes to atherosclerosis through endothelial dysfunction and oxidative stress. Folic acid, a key cofactor in homocysteine metabolism, has been proposed as a preventive strategy. However, recent studies have provided conflicting evidence regarding its effectiveness in preventing cardiovascular outcomes beyond stroke. Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, we conducted a search in multiple databases, including PubMed, Cochrane, Scopus, Web of Science, CINAHL, and EMBASE, and pre-registered on PROSPERO: CRD42024525945. Data were pooled using a random-effects model in R (version 3.4.3), with relative risks (RRs), mean differences (MD) and 95% confidence intervals (CIs) calculated. Our search yielded a preliminary list of 25,881 articles, with 45 studies that includes 96,962 participants meeting the inclusion criteria. These studies evaluated the effectiveness of folic acid supplementation in preventing cardiovascular disease and related events. The meta-analysis showed that folic acid supplementation reduced the risk of stroke (RR = 0.85, 95% CI: 0.76–0.96, p < 0.01) and modest reduction on overall CVD (RR = 0.95, 95% CI: 0.90–0.99, p = 0.04). No significant effects were found for mortality (RR = 0.98, 95% CI: 0.93–1.02), CHD (RR = 0.98, 95% CI: 0.91–1.06), PAD (RR = 0.94, 95% CI: 0.75–1.17), HDL (MD = 0.31, 95% CI: -0.04–0.65), or LDL (MD = -1.59, 95% CI: -8.82–5.64). These findings reveal the capability of folic acid supplementation in reducing the risk of stroke and cardiovascular disease. However, no benefit was found for other cardiovascular endpoints. These findings support folic acid’s targeted use in primary prevention strategies, but further research is needed to refine patient selection and clarify its role in broader cardiovascular risk management. 1. Stroke Risk Reduction: Folic acid supplementation significantly reduces stroke risk but has no significant effect on cardiovascular disease, coronary heart disease, or peripheral arterial disease. 2. No Effect on Lipid Profiles: Folic acid supplementation does not significantly impact high-density lipoprotein (HDL) or low-density lipoprotein (LDL) levels. 3. Study Variability and Bias: There is substantial heterogeneity and some high-risk biases across the studies included, which suggests the need for careful interpretation of the results. 4. Further Research Needed: The findings underscore the necessity for additional research to better understand how folic acid supplementation might more broadly influence cardiovascular health.