Work

The Bad Reputation of Digoxin in Atrial Fibrillation—Causality or Bias? Nationwide Nested Case-Control Study

Year: 2025

Type: article

Abstract: • The use of digoxin in atrial fibrillation and heart failure has decreased in the last decade • Associations between digoxin use and poorer cardiovascular outcomes were found • Associations between digoxin and pneumonia and nursing home admission were also found • It is reassuring that recent findings of increased mortality may be explained by confounding • If causal associations exist between digoxin use and increased mortality should be explored further Studies have reported excess risk of mortality associated with digoxin in atrial fibrillation (AF). This study sought to investigate if these findings could be replicated and whether a potential association could be explained by bias. Using Danish Nationwide registers, a nested-case control study from 2012–2022 was conducted in a cohort of patients with AF. Cases were defined as death of any cause and the exposure was treatment with digoxin compared with beta blockers/verapamil. To investigate bias, additional analyses with negative control outcomes as case definitions—in which we would not expect a plausible association (e.g., nursing home admission)—were employed. Associations were reported as hazard ratios (HRs) with 95% confidence intervals (95% CI). A total of 59,748 cases were identified and matched 1:10 with controls (53% men, median age: 84 [IQR: 77–89]). Digoxin was associated with increased rates of mortality in the entire cohort (HR 1.85, 95% CI 1.78–1.92) as well as subgroups such as patients with heart failure (HR 1.84, 95% CI 1.65–2.06), diabetes (HR 1.85, 95% CI 1.6–2.14), and kidney disease (HR 1.37, 95% CI 1.04–1.8). Significant associations with all negative control outcomes were also found, most notably nursing home admissions (HR 1.79, 95% CI 1.67–1.93). Digoxin use was associated with increased mortality in AF. However, negative control outcomes were also associated with digoxin use indicating that the described association between digoxin and mortality is likely not causal and being prescribed digoxin is merely a marker of more advanced disease and frailty.

Source: American Journal of Medicine Open

DOI: 10.1016/j.ajmo.2025.100093

Authors: Anders Holt, Jarl Emanuel Strange, Morten Lock Hansen, Morten Lamberts, Peter Vibe Rasmussen

Institutions: Herlev Hospital, Gentofte Hospital, University of Copenhagen

Language: English

Topic: Atrial Fibrillation Management and Outcomes

Subfield: Cardiology and Cardiovascular Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,540