ArticlesDigoxin 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)
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.
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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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