Effect of digoxin on all-cause and cardiovascular mortality in patients with atrial fibrillation with and without heart failure: an umbrella review of systematic reviews and 12 meta-analyses

Purpose: To perform a systematic umbrella review with meta-analysis to evaluate the certainty of evidence on mortality risk associated with digoxin use in patients with atrial fibrillation (AF) with or without heart failure (HF). Methods: We systematically searched MEDLINE, Embase, and Web of Science databases from inception to 19 October 2021. We included systematic reviews and meta-analyses of observational studies investigating digoxin effects on mortality of adult patients with AF and/or HF. The primary outcome was all-cause mortality; secondary outcome was cardiovascular mortality. Certainty of evidence was evaluated by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool and the quality of systematic reviews/meta-analyses by the A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR2) tool. Results: Eleven studies accounting for 12 meta-analyses were included with a total of 4,586,515 patients. AMSTAR2 analysis showed a high quality in 1, moderate in 5, low in 2, and critically low in 3 studies. Digoxin was associated with an increased all-cause mortality (hazard ratio [HR] 1.19, 95% confidence interval [95%CI] 1.14–1.25) with moderate certainty of evidence and with an increased cardiovascular mortality (HR 1.19, 95%CI 1.06–1.33) with moderate certainty of evidence. Subgroup analysis showed that digoxin was associated with all-cause mortality both in patients with AF alone (HR 1.23, 95%CI 1.19–1.28) and in those with AF and HF (HR 1.14, 95%CI 1.12–1.16). Conclusion: Data from this umbrella review suggests that digoxin use is associated with a moderate increased risk of all-cause and cardiovascular mortality in AF patients regardless of the presence of HF. Trial registration: This review was registered in PROSPERO (CRD42022325321).