Elsevier

Heart Rhythm

Volume 11, Issue 9, September 2014, Pages 1543-1550
Heart Rhythm

Digoxin in patients with permanent atrial fibrillation: Data from the RACE II study

https://doi.org/10.1016/j.hrthm.2014.06.007Get rights and content

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 cardiovascular (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. Outcome 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.

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 lifestyle.2, 3, 4, 5 There are, however, no double-blind, randomized studies that have investigated the effectiveness of digoxin as a rate control drug, nor the effect on outcome in patients with AF.

Until now, only 1 randomized trial (Digitalis Investigation Group [DIG] trial) in patients with HF showed that digoxin did not reduce mortality.6 In 2004, the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial reported that digoxin was independently associated with increased mortality in patients with AF.7 More recently, 2 additional post hoc analyses of the AFFIRM trial on the effect of digoxin were conducted and reported conflicting results of its effect on prognosis.8, 9 The AFFIRM trial encouraged uptitrating digoxin with high serum concentrations until the heart rate target was achieved,10 which is in contrast to the instructions for instituting rate control drugs in the Rate Control Efficacy in Permanent AF: A Comparison between Lenient versus Strict Rate Control II (RACE II) trial.11 Since digoxin has a narrow therapeutic index, it was prescribed at low dosages in the RACE II trial.2, 12, 13, 14, 15, 16 This may have led to a different outcome as compared to the results of the AFFIRM trial.

We therefore assessed whether the use of digoxin in patients included in the RACE II trial was associated with cardiovascular morbidity and mortality and whether digoxin increased the number of patients achieving the heart rate targets.14

Section snippets

Study population

This analysis includes 608 of 614 patients (99%) randomized into the RACE II trial who completed the dose-adjustment phase.17 Patients were stratified by the use of digoxin after the dose-adjustment phase. The study design, patient characteristics, and results of the RACE II trial have been published previously.11, 14, 17, 18, 19, 20 In short, the RACE II trial was a randomized multicenter study comparing long-term effects of lenient vs strict rate control on morbidity and mortality in 614

Baseline characteristics

Of 608 of 614 patients (99%) completing the dose-adjustment phase in the RACE II trial, 196 (32.2%) were treated with digoxin at baseline and 284 (46.7%) used digoxin after the dose-adjustment phase (median dosage 0.250 mg; interquartile range 0.0625–0.750 mg). Twenty-six patients (9.2%) used digoxin as the only rate control drug, 160 (60.2%) used it in combination with a β-blocker, and 84 (30.6%) in combination with other drugs (Table 1). Patients with digoxin were more often women, more often

Discussion

The present post hoc analysis of the RACE II trial shows that in patients with permanent AF, digoxin use was not associated with an impaired outcome.

Conclusion

In patients enrolled in the RACE II trial with permanent AF and without severe HF, the use of digoxin was not associated with increased cardiovascular morbidity and mortality. Therefore, the present results support the use of digoxin in eligible patients with permanent AF when digoxin is instituted with caution.

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  • Cited by (0)

    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, Medtronic, Roche, and Sanofi-Aventis France (paid to the Interuniversity Cardiology 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.

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