Therapeutic Drug Monitoring of Direct Oral Anticoagulants and Its Association with Clinical Outcomes: A Systematic Review and Meta-Analysis

<b>Background:</b> Direct oral anticoagulants (DOACs) are now the preferred anticoagulant over vitamin K antagonists for patients with atrial fibrillation (AF) and venous thromboembolism (VTE). Variability in drug exposure raises concerns about bleeding and thrombotic events, highlighting the potential value of therapeutic drug monitoring (TDM). <b>Methods:</b> This systematic review and meta-analysis conducted a systematic search of PubMed, Embase, Web of Science, Scopus, Cochrane Library, and ClinicalTrials.gov (from inception to May 2025) and identified studies reporting DOAC levels and clinical outcomes. Two reviewers independently performed screening, data extraction, and risk-of-bias assessment (RoB 2.0, Newcastle-Ottawa Scale). Random-effects meta-analytical models generated pooled estimates, with meta-regression exploring potential sources of variability (DOAC type, drug levels) and exposure-response relationships. <b>Results:</b> Nineteen studies comprising 5770 patients were included in the review. The pooled event rates were 8% for major bleeding (95% CI: 0.05-0.11), 7% for thrombotic events (95% CI: 0.05-0.09), and 3% for mortality (95% CI: 0.03-0.04). Heterogeneity was substantial for bleeding and thrombotic events (<i>I</i>² = 95.6% and 87.3%, respectively) but negligible for mortality (<i>I</i>² = 0%). Meta-regression analyses showed no significant association between mean DOAC concentration and either major bleeding (β = -0.00021, <i>p</i> = 0.35, Adj R² ≈ 0%) or thrombotic events (β = 0.00005, <i>p</i> = 0.78, Adj R² ≈ 0%), indicating that variations in measured plasma levels did not meaningfully explain event rate differences across studies. <b>Conclusions:</b> In this systematic review and meta-analysis, measured DOAC concentrations show limited and inconsistent association with clinical outcomes. While the present synthesis does not demonstrate a statistically robust linear correlation between DOAC plasma concentrations and adverse outcomes, it highlights the multifactorial determinants of bleeding and thrombosis risk underscores the potential value of selective TDM in individualized care. Further prospective, standardized studies are needed to define clinically actionable thresholds and to validate TDM-guided strategies that optimize the delicate balance between safety and efficacy in DOAC therapy.