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Background: Direct oral anticoagulants (DOACs) have been increasingly used as anticoagulation therapy in the postoperative period. However, their effectiveness in post-cardiac surgical atrial fibrillation is yet to be determined.Methods: We conducted a meta-analysis, searching three international databases from 1 January 2003 to 26 January 2022 for studies reporting on DOACs in at least 10 adult patients (>18 yr of age) with post-cardiac surgical atrial fibrillation. The primary outcomes were major neurological events and bleeding; secondary outcomes were mortality, hospital and ICU length of stay, cost, and other complications from therapy. We included studies of any design, including RCTs, cohort studies with and without propensity score matching methods, and single-armed case series.Results: Twelve studies (8587 DOACs; 8315 warfarin) were included in this meta-analysis. The incidences of postoperative bleeding and major neurological events with DOACs were 7.3% (95% confidence interval [CI]: 3.4-14.7%) and 2.2% (95% CI: 0.9-4.9%), respectively. The incidence of major neurological events was lower in high-risk patients, including those with hypertension and higher CHA2DS2-VASc score, whereas patients with prior transient ischaemic attack or stroke had higher incidence of bleeding. Trial sequential analysis revealed that the cumulative Z-curve crossed the conventional boundary of benefit. Compared with warfarin, DOACs reduced the risk of bleeding (relative risk [RR] 0.74; 95% CI: 0.62-0.89; P=0.0011) and major neurological events (RR 0.63; 95% CI: 0.48-0.83; P=0.0012) but not mortality (RR 1.02; 95% CI: 0.77-1.35; P=0.090).Conclusions: DOACs reduced bleeding and major neurological events in patients with post-cardiac surgical atrial fibrillation, appearing safer than warfarin in this context. However, which specific DOAC provides the most effective anticoagulation in this patient population needs further investigation.Clinical Trial Registration: PROSPERO CRD42021282777. [ABSTRACT FROM AUTHOR]