Digoxin in patients with permanent atrial fibrillation: Data from the RACE II study Bart A. Mulder, MD, * Dirk J. Van Veldhuisen, MD, PhD, * Harry J.G.M. Crijns, MD, PhD, † Jan G.P. Tijssen, PhD, ‡ Hans L. Hillege, MD, PhD, § Marco Alings, MD, PhD, ║ Michiel Rienstra, MD, PhD, * Maarten P. Van den Berg, MD, PhD, * Isabelle C. Van Gelder, MD, PhD, *¶ for the RACE II Investigators From the * Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands, † Department of Cardiology, Maastricht University Medical Center, Maastricht, The Netherlands, ‡ Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands, § Trial Coordination Center, Department of Epidemiology, University Medical Center Groningen, Groningen, The Netherlands, ║ Department of Cardiology, Amphia Hospital, Breda, The Netherlands, and ¶ Interuniversity Cardiology Institute Netherlands, Utrecht, The Netherlands. BACKGROUND The Atrial Fibrillation Follow-up Investigation of Rhythm Management trial showed that digoxin was associated with increased mortality in patients with atrial fibrillation. OBJECTIVES To assess the association of digoxin with cardiovas- cular (CV) morbidity and mortality in patients with permanent atrial fibrillation enrolled in the Dutch Rate Control Efficacy in Permanent AF: A Comparison Between Lenient Versus Strict Rate Control II trial as well as to assess the role of digoxin to achieve heart rate targets. METHODS The primary outcome was a composite of CV morbidity and mortality. Secondary outcomes included CV hospitalization and all-cause mortality or heart failure (HF) hospitalization. Of the 614 patients, 608 (99%) completed the dose-adjustment phase. Out- come events were analyzed from the end of the dose-adjustment phase until the end of follow-up. The median follow-up period was 2.9 years (interquartile range 2.7–3.0 years). RESULTS In total, 284 patients (46.7%) used digoxin after the dose-adjustment phase (median dosage 0.250 mg; interquartile range 0.0625–0.750 mg). These patients were more often women, previously admitted for HF, had an increased left ventricular end- systolic diameter, and more often randomized to strict rate control. By using Cox proportional hazards regression analysis, the use of digoxin was not associated with an increased risk for the primary and secondary outcomes. For the primary outcome, the 3-year estimated cumulative incidence was 12.9% vs 13.4% in the digoxin group vs the no-digoxin group (unadjusted hazard ratio [HR] 0.97; 95% confidence interval [CI] 0.62–1.52). Incidence was 19.4% vs 19.5% for CV hospitalization (unadjusted HR 1.00; 95% CI 0.69– 1.45) and 6.6% vs 9.9% for all-cause mortality or HF hospitalization (unadjusted HR 0.62; 95% CI 0.34–1.13) in the digoxin group vs the no-digoxin group. CONCLUSION The use of digoxin was not associated with increased morbidity and mortality. KEYWORDS Atrial fibrillation; Digoxin; Morbidity; Mortality; Rate control ABBREVIATIONS AF ¼ atrial fibrillation; AFFIRM ¼ Atrial Fibrillation Follow-Up Investigation of Rhythm Management; CI ¼ confidence interval; DIG ¼ Digitalis Investigation Group; HF ¼ heart failure; HR ¼ hazard ratio; NT-proBNP ¼ N-terminal prohormone of brain natriuretic peptide; RACE II ¼ Rate Control Efficacy in Permanent AF: A Comparison Between Lenient Versus Strict Rate Control II (Heart Rhythm 2014;11:1543–1550) I 2014 Heart Rhythm Society. All rights reserved. Introduction Digoxin is often administered as a rate control drug in the treatment of atrial fibrillation (AF) in patients with or without heart failure (HF). 1 Recent guidelines support the use of digoxin especially for rate control in patients with AF and an inactive Participants in the RACE II trial for permanent atrial fibrillation are listed elsewhere (see Reference 14). The RACE II study was supported by the Netherlands Heart Foundation (2003B118) and Interuniversity Cardiology Institute, The Netherlands, and by unrestricted educational grants from AstraZeneca, Biotronik, Boehringer Ingelheim, Boston Scientific, Medtro- nic, Roche, and Sanofi-Aventis France (paid to the Interuniversity Cardiol- ogy Institute of the Netherlands). Dr Van Veldhuisen has received board membership fees from Amgen, Vifor, BG Medicine, Sorbent, Johnson & Johnson, and Biocontrol. Dr Crijns has received consulting fees from Boehringer Ingelheim, Sanofi-Aventis, and AstraZeneca; grant support from St Jude Medical, Boston Scientific, Boehringer Ingelheim, Sanofi-Aventis, Medapharma, and Merck; and honoraria from Medtronic, Sanofi-Aventis, Medapharma, Merck, Boehringer Ingelheim, and Biosense Webster. Dr Alings has received consulting fees from Boehringer Ingelheim and Sanofi- Aventis. Dr Van Gelder has received consulting fees from Sanofi-Aventis, Boehringer Ingelheim, and Cardiome; grant support from Medtronic, Biotronik, and St Jude Medical; and lecture fees from Sanofi-Aventis, Boehringer Ingelheim, and Medtronic. Address reprint requests and correspondence: Dr Isabelle C. Van Gelder, Department of Cardiology, Thoraxcenter, University of Groningen, University Medical Center Gronin- gen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. E-mail address: i.c.van.gelder@umcg.nl. 1547-5271/$-see front matter B 2014 Heart Rhythm Society. All rights reserved. http://dx.doi.org/10.1016/j.hrthm.2014.06.007