Reconsidering Digoxin in Atrial Fibrillation: From Historical Controversy to Physiologically Guided and Personalized...

Background: The role of digoxin in atrial fibrillation, particularly in patients with heart failure, has long been debated. Observational studies reporting higher mortality have fueled skepticism, yet growing evidence suggests that these findings largely reflect prescription bias, confounding by indication, and inadequate adjustment for serum-level rather than intrinsic toxicity. Objective: To reassess digoxin's role in atrial fibrillation with heart failure using contemporary evidence and to propose a physiology-based, personalized monitoring framework. Evidence review: We reevaluated the studies that initially linked digoxin to excess mortality and reassessed these associations through three analytic pillars: randomized evidence, bias deconstruction, and exposure-response relationships. Across datasets, low serum digoxin concentrations were consistently associated with stable resting rate control without increasing mortality. Key findings: Low-dose, continuously administered digoxin is a viable second-line option for atrial fibrillation rate control in patients who are hypotensive or intolerant of β-blockers. Safety is concentration-dependent; adverse outcomes increase at higher serum digoxin concentration (≥1.2 ng/mL). Resting heart rate can serve as a contextual surrogate of exposure: persistent HR > 100 bpm in stable patients usually reflects underexposure rather than digoxin toxicity, whereas bradycardia should prompt immediate serum digoxin concentration testing. Proposal: A probability-based monitoring model that integrates heart rate, renal function, dosage, electrolytes, and drug-drug interactions to guide when serum digoxin concentration measurement is warranted. As a future direction, a supervised "pill-in-the-pocket" supplemental dose strategy could be evaluated for transient tachycardia in selected, stable patients. Conclusions: When properly dosed and contextually monitored, digoxin remains a safe, effective, and individualized rate-control option in atrial fibrillation with heart failure. Prospective validation of probability-guided monitoring and evaluation of a "pill-in-the-pocket" approach could simplify digoxin management while maintaining safety.