Original Investigation
Digoxin and Mortality in Patients With Atrial Fibrillation

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Abstract

Background

Digoxin is widely used in patients with atrial fibrillation (AF).

Objectives

The goal of this paper was to explore whether digoxin use was independently associated with increased mortality in patients with AF and if the association was modified by heart failure and/or serum digoxin concentration.

Methods

The association between digoxin use and mortality was assessed in 17,897 patients by using a propensity score–adjusted analysis and in new digoxin users during the trial versus propensity score–matched control participants. The authors investigated the independent association between serum digoxin concentration and mortality after multivariable adjustment.

Results

At baseline, 5,824 (32.5%) patients were receiving digoxin. Baseline digoxin use was not associated with an increased risk of death (adjusted hazard ratio [HR]: 1.09; 95% confidence interval [CI]: 0.96 to 1.23; p = 0.19). However, patients with a serum digoxin concentration ≥1.2 ng/ml had a 56% increased hazard of mortality (adjusted HR: 1.56; 95% CI: 1.20 to 2.04) compared with those not on digoxin. When analyzed as a continuous variable, serum digoxin concentration was associated with a 19% higher adjusted hazard of death for each 0.5-ng/ml increase (p = 0.0010); these results were similar for patients with and without heart failure. Compared with propensity score–matched control participants, the risk of death (adjusted HR: 1.78; 95% CI: 1.37 to 2.31) and sudden death (adjusted HR: 2.14; 95% CI: 1.11 to 4.12) was significantly higher in new digoxin users.

Conclusions

In patients with AF taking digoxin, the risk of death was independently related to serum digoxin concentration and was highest in patients with concentrations ≥1.2 ng/ml. Initiating digoxin was independently associated with higher mortality in patients with AF, regardless of heart failure.

Key Words

atrial fibrillation
digoxin
heart failure
mortality

Abbreviations and Acronyms

AF
atrial fibrillation
CI
confidence interval
GDF
growth differentiation factor
HR
hazard ratio
LVEF
left ventricular ejection fraction

Cited by (0)

The ARISTOTLE study was funded by Bristol-Myers Squibb, and Pfizer. This analysis was supported by the Duke Clinical Research Institute, Bristol-Myers Squibb, Pfizer, and, in part, by grant R03 HS24310 from the Agency for Healthcare Research and Quality (AHRQ). All analyses were conducted at the Duke Clinical Research Institute and the Uppsala Clinical Research Center, and the authors had full access to all data. The Duke Clinical Research Institute coordinated the trial and managed the database. An academic steering committee designed the trial and was responsible for oversight of study conduct and reporting of all results, and takes responsibility for the accuracy and completeness of the data analyses. The authors are fully responsible for the study design, data collection, analysis and interpretation of the data, and writing of the manuscript; all authors agreed to submit the manuscript for publication. The sponsor played no role in the decision to submit the manuscript for publication. Dr. Lopes has received research grants from Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, and Pfizer; and consulting fees/honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Medtronic, Merck & Co., Pfizer, and Portola. Dr. Rordorf has received speaking fees from Medtronic and St. Jude Medical. Dr. De Ferrari has received research grant support from Amgen; advisory board and speaking fees from Amgen, Merck, and Sigma-Tau; and steering committee support from Boston Scientific. Dr. Leonardi has received research grant support from AstraZeneca; and honoraria from The Medicines Company, Chiesi, Daiichi-Sankyo, and AstraZeneca. Dr. Lawrence was an employee of Bristol-Myers Squibb at the time of the trial. Dr. De Caterina has received research grants, consulting fees, and honoraria from Sanofi, Boehringer Ingelheim, Bayer, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Novartis, and Merck. Dr. Vinereanu has received research grants from Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, Johnson & Johnson, and Bayer; and consulting/honoraria fees from Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, and Bayer. Dr. Hanna was an employee of Bristol-Myers Squibb at the time of the trial. Dr. Hohnloser has received consulting fees from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Johnson & Johnson, Pfizer, Medtronic, and St. Jude Medical; and lecture fees from Boehringer Ingelheim, Bayer, Bristol-Myers Squibb, Pfizer, and Abbott. Dr. Alexander has received research grants from Bristol-Myers Squibb, Boehringer Ingelheim, CSL Behring, Sanofi, and Tenax Therapeutics; and consulting fees/honoraria from Cempra, CryoLife, CSL Behring, Pfizer, Portola Pharmaceuticals, and VasoPrep Surgical. Dr. Granger has received research grants from Armetheon, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Janssen Pharmaceuticals, Medtronic Foundation, Novartis Corporation, Pfizer, and The Medicines Company; and consulting fees/honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Gilead Sciences, Inc., GlaxoSmithKline, Hoffmann-La Roche, Janssen, Medtronic Inc., Novartis, Pfizer, The Medicines Company, and Verseon. Dr. Wallentin has received research grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Merck/Schering-Plough, Pfizer, and Roche Diagnostics; and consulting fees/honoraria from Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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