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In 2002, The Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial showed no difference between rate control versus rhythm control. Despite the fact that the AFFIRM was looking at whether rate or rhythm control produced a better outcome for patients, not whether digoxin is beneficial or harmful, Whitbeck et al1 did a post hoc analysis from this study to determine the relationship between digoxin and mortality in patients with atrial fibrillation (AF).

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The focus of the analysis was to evaluate the relationship between lower doses of digoxin and mortality since the literature supports the association between higher digoxin levels and mortality. The only data to support this association between higher doses and mortality came from a sub-study of the Digitalis Investigation Group (DIG) trial in which the main intention-to-treat (ITT) analysis failed to demonstrate a mortality reduction with digoxin.(2) The results of the DIG trial indicated that digoxin did not reduce overall mortality (34.8%) in digoxin group versus (35.1%) in placebo group (RR:0.99, CI:0.91–1.07; p value= 0.8). However, there was a significant reductions in number of hospitalizations (6% fewer) and less worsening of heart failure (about 8% fewer) in the digoxin group.1,2

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The authors of this study sought to  examine the effects of digoxin on all-cause mortality (primary endpoint) and on hospitalization from heart failure (major secondary endpoint) in patients left ventricular ejection fraction (EF) <0.45 with normal sinus rhythm.1 After adjustment for clinical risk factors, comorbidities, and propensity scores, digoxin was independently associated with a 41% increase in all cause mortality in patients without or with HF (hazard ratio [HR] 1.37, 95% CI 1.05–1.79; p = 0.019 and HR,1.41, 95% CI 1.09–1.84, P = 0.010, respectively), 35% higher risk of deaths from cardiovascular causes/cardiovascular mortality (HR 1.35, 95% CI 1.06–1.71; p= 0.016), and 61% increase in arrhythmic mortality (HR 1.61, 95% CI 1.12–2.30; p = 0.009). The all-cause mortality remained higher with the use of digoxin among patients with and without HF. There was no significant digoxin-gender interaction noted and the increase in all-cause mortality was observed in both men and women. 1

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It appears reasonable to conclude that the widespread use of digoxin should be questioned in patients with atrial fibrillation regardless of gender or the presence or absence of HF. In light of the concerns raised by the AFFIRM trial and other studies, it also appears reasonable to discourage rate control with digoxin as a single first line agent, especially when other safe and inexpensive alternatives such as beta blockers or calcium blockers are readily available. 2

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In summary, digoxin might be less effective than beta blockers and calcium channel blockers for rate control, the use of digoxin in AF patients significantly increased all cause mortality independent of gender and the presence or absence of HF.

1. Whitbeck M, Charnigo R, Khairy P. at al. Increased mortality among patients taking digoxin—analysis from the AFFIRM study. Eur Heart J. 2013;34(20):1481–88. ...

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