Atrial fibrillation (AF) is the most common cardiac arrhythmia. The burden of AF also seems to be an important factor for heart failure (HF). Digoxin has been used in clinical practice for long-time treating AF patients with and without HF for heart rate control. DIG trial only included HF patients with sinus rhythm, and these results cannot be extended to patients with AF. Recently, some observational studies have shown that digoxin was associated with increased mortality in AF patients, but this was not supported by other studies. Some recently published meta-analyses also reported conflicting conclusions.



Search Strategy and Selection Criteria

As per the Meta-Analysis of Observational Studies in Epidemiology Group, the electronic databases, including PubMed, EMBASE, and the Cochrane Library were searched for studies to August 31, 2015, using a combined text and MeSH heading search strategy with the terms “digitalis” or “digoxin” or “digitoxin” or “cardiac glycosides” and “mortality,” “death,” “deaths” or “fatal,” and “atrial fibrillation.” The search was restricted to human studies, but there were no language or publication form restrictions. 

Data Extraction, Synthesis, and Analysis

Two investigators (YC and XC) independently conducted literature searches reviewed the potential articles, and abstracted data from eligible studies. Discrepancies were resolved by discussion with other investigators (YulH and YunH).



Studies Retrieved and Characteristics

Overall, 2082 manuscripts were initially retrieved. After screening titles and abstracts, 31 qualified for a full review. Finally, 17 articles comprising 408,660 patients were included in this study. There were 3 reports from the Atrial Fibrillation Follow-Up Investigation of Rhythm Management study. In which report by Whitbeck et al26 for the primary analysis was included as it employed more rigorous analytic methodology, including defined digoxin treatment as baseline treatment, time-dependent covariates, and propensity score-matched analysis.

All-Cause Mortality in Digoxin Treatment Was Modified by Heart Function

Eight studies reported the risk of all-cause mortality in AF patients with or without HF, and studies reported data for AF patients with HF but did not include data for those without HF, while 2 other studies only supplied data for AF patients without HF. Pooled data from these studies showed that digoxin treatment was associated with a 14% increase of all-cause mortality in AF patients with HF) and a 36% increase in those without HF. There was a significant difference in risk in AF patients with and without HF. For detailed review and analysis refer to the full documentation.



As per analysis in AF patients, digoxin treatment was associated with a 22% increase in all-cause mortality. The risk was mildly increased in AF patients with HF, but much more pronounced in those without HF. In a meta-analysis concerning the safety of digoxin treatment in observational and controlled trial data, and reported that in data from RCTs, digoxin had a neutral effect on mortality. It should be noted that data from RCTs included in this study were based on HF patients with sinus rhythm and largely driven by the DIG trial.

However, the biological or clinical rationale for digoxin treatment may be different in AF patients compared with those with sinus rhythm. Therefore, conclusions from patients with sinus rhythm cannot be extended to AF patients.

A criticism is that observational studies are inherently not experimental and could not draw firm conclusions from such studies. As RCTs are needed to further evaluate the role of digoxin in AF patients. However, it seems that such RCTs are unlikely to be performed. Large-sample observational studies can provide valuable information and are critical to answer relevant questions in real-world practice and to help choose treatment strategies.

In real-world practice, digoxin treatment was associated with increased mortality in AF patients, especially in those without HF. In these patients, digoxin was mainly used for heart rate control. Given other available drugs for heart rate control, such as nondihydropyridine calcium channel antagonists and beta-blockers, digoxin should be used with caution in the management of AF, especially in those without HF.

In conclusion, the study showed that digoxin therapy was associated with a significant increase in all-cause mortality in AF patients, especially in those without HF. Given other available treatment options, clinicians should avoid using digoxin as a first-line agent for heart rate control in AF patients. 



Disease Condition ,Therapeutic Modality ,Arrhythmias,Pharmacotherapeutics,Atrial Fibrillation,Digitalis