Objective: Postmarketing observational studies report that a substantial percentage of patients with atrial fibrillation (AF) receive a reduced non-vitamin K antagonist oral anticoagulant (NOAC) dose without a clear indication. Recently, increasing evidence has become available to explore the clinical consequences of such off-label reduced dosing (OLRD). This study aims to systematically review and meta-analyse observational studies that report clinical outcomes associated with OLRD of NOACs compared with on-label non-reduced dosing (OLNRD) of NOACs in patients with AF., Methods and Analysis: We performed a systematic literature review and meta-analysis of observational studies reporting clinical outcomes in AF patients with OLRD of an NOAC compared with AF patients with OLNRD of an NOAC. Using random effects meta-analyses, we estimated the risk of stroke/thromboembolism, bleeding and all-cause mortality., Results: We included 19 studies with a total of 170 394 NOAC users. In these studies, the percentage of OLRD among patients with an indication for an on-label non-reduced NOAC dose ranged between 9% and 53%. 7 of these 19 studies met the predefined criteria for meta-analysis (n=80 725 patients). The pooled HR associated with OLRD of NOACs was 1.04 (95% CI 0.83 to 1.29; 95% prediction interval (PI) 0.60 to 1.79) for stroke/thromboembolism, 1.10 (95% CI 0.95 to 1.29; 95% PI 0.81 to 1.50) for bleeding and 1.22 (95% CI 0.81 to 1.84; 95% PI 0.55 to 2.70) for all-cause mortality., Conclusion: This meta-analysis shows no statistically significant increased risk of stroke/thromboembolism, nor a decreased bleeding risk, nor a difference in risk of all-cause mortality in patients with OLRD of NOACs. Future research may focus on differences between NOACs., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/. FR, MH and G-JG report unrestricted institutional grants for performing research in the field of atrial fibrillation from Boehringer-Ingelheim, Bayer Healthcare, BMS Pfizer and Daiichi Sankyo. CBG reports personal fees from Bayer Healthcare and Boston Scientific; grants and personal fees from Boehringer-Ingelheim, BMS Pfizer and Janssen; and grants from Daiichi-Sankyo during the conduct of the study; personal fees from AbbVie, Espero, Medscape, Medtronic, Merck, the National Institutes of Health, Novo Nordisk, Roche, Rho Pharmaceuticals, CeleCor, Correvio, Philips, Abiomed and Anthos Therapeutics; grants from Akros, AstraZeneca, the US Food and Drug Administration, Glaxo Smith Kline, Medtronic Foundation and Apple; and grants and personal fees from Novartis and The Medicines Company outside the submitted work. SvD reports an unrestricted research grant from Stoffels Hornstra. All other authors (LJ, RvM, CJvdD and AWH) declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear tohave influenced the submitted work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)