Elsevier

The Lancet

Volume 385, Issue 9985, 13–19 June 2015, Pages 2363-2370
The Lancet

Articles
Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF)

https://doi.org/10.1016/S0140-6736(14)61836-5Get rights and content

Summary

Background

Digoxin is a widely used drug for ventricular rate control in patients with atrial fibrillation (AF), despite a scarcity of randomised trial data. We studied the use and outcomes of digoxin in patients in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF).

Methods

For this retrospective analysis, we included and classified patients from ROCKET AF on the basis of digoxin use at baseline and during the study. Patients in ROCKET AF were recruited from 45 countries and had AF and risk factors putting them at moderate-to-high risk of stroke, with or without heart failure. We used Cox proportional hazards regression models adjusted for baseline characteristics and drugs to investigate the association of digoxin with all-cause mortality, vascular death, and sudden death. ROCKET AF was registered with ClinicalTrials.gov, number NCT00403767.

Findings

In 14 171 randomly assigned patients, digoxin was used at baseline in 5239 (37%). Patients given digoxin were more likely to be female (42% vs 38%) and have a history of heart failure (73% vs 56%), diabetes (43% vs 38%), and persistent AF (88% vs 77%; p<0·0001 for each comparison). After adjustment, digoxin was associated with increased all-cause mortality (5·41 vs 4·30 events per 100 patients-years; hazard ratio 1·17; 95% CI 1·04–1·32; p=0·0093), vascular death (3·55 vs 2·69 per 100 patient-years; 1·19; 1·03–1·39, p=0·0201), and sudden death (1·68 vs 1·12 events per 100 patient-years; 1·36; 1·08–1·70, p=0·0076).

Interpretation

Digoxin treatment was associated with a significant increase in all-cause mortality, vascular death, and sudden death in patients with AF. This association was independent of other measured prognostic factors, and although residual confounding could account for these results, these data show the possibility of digoxin having these effects. A randomised trial of digoxin in treatment of AF patients with and without heart failure is needed.

Funding

Janssen Research & Development and Bayer HealthCare AG.

Introduction

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice, estimated to currently affect more than 30 million people worldwide.1, 2 It is associated with increased risk of stroke, heart failure, cognitive impairment, and death, and complicates management of other disorders.3 A key treatment goal in AF is heart rate control, which can help to reduce symptoms and the risk of cardiomyopathy.4 Rate control is often achieved with one or more drugs from several classes, including β blockers, non-dihydropyridine calcium channel antagonists, and digoxin. Present American Heart Association, American College of Cardiology, and Heart Rhythm Society treatment guidelines for management of AF1 provide a class I recommendation (level of evidence C) for digoxin treatment as being effective for resting heart rate control in patients with heart failure and reduced left ventricular ejection fraction. A class IIa recommendation (level of evidence B) is made for use of digoxin in combination with either a β blocker or non-dihydropyridine calcium channel antagonist for patients with heart failure and preserved ejection fraction to control heart rate at rest and during exercise.1 Present European Society of Cardiology guidelines for management of AF provide a class IIa recommendation (level of evidence C) for digoxin as a long-term rate control drug in patients with heart failure and left ventricular dysfunction, and in sedentary patients.5

Although digoxin has been assessed in a large randomised clinical trial of heart failure patients without AF,6 randomised trials assessing the use of digoxin for AF are scarce. Additionally, observational studies designed to assess the effect of digoxin treatment on outcomes in patients with AF have produced inconsistent results.7, 8, 9, 10, 11 Additional data from contemporary studies of patients with AF are therefore needed to inform clinical practice.

In this post-hoc analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF),12, 13 we sought to assess cardiovascular outcomes associated with digoxin treatment in patients with AF, including those with and without heart failure.

Section snippets

Study design and participants

We undertook a retrospective analysis of data from ROCKET AF, a multicentre, randomised, double-blind, double-dummy, event-driven trial comparing fixed-dose rivaroxaban (20 mg once daily or 15 mg once daily in patients with creatinine clearance 30–49 mL/min) with adjusted-dose warfarin (target international normalised ratio 2·0–3·0) for prevention of all stroke (ischaemic or haemorrhagic) or systemic embolism, as described elsewhere.12

Patients with electrocardiographically documented

Results

In ROCKET AF, 5239 (37%) of 14 171 patients were on digoxin at time of randomisation. Table 1 provides baseline characteristics of patients given digoxin versus those who were not. Patients with AF given digoxin were significantly more likely to be female, have a history of heart failure, have diabetes, and have persistent AF than those who were not (table 1). These patients also tended to have a higher baseline heart rate than those not given digoxin (table 1). Patient characteristics

Discussion

The findings of this post-hoc analysis of ROCKET AF suggest that digoxin treatment is associated with an increase in the risk of all-cause mortality, vascular death, and sudden death in patients with AF. This increased risk was present after adjustment for baseline variables, adjustment with inverse probability weighting for propensity for baseline digoxin use, and time-dependent adjustment for digoxin use during the study. Additionally, we noted no significant digoxin–heart failure interaction

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