A Cochrane review [Abstract] 1 included 13 studies with a total of 7 896 subjects. The aim of the review was to examine the effectiveness of digitalis glycosides in treating heart failure (HF) in patients with normal sinus rhythm. Treatment with digoxin had no effect on death rates (OR 0.98, 95% CI 0.89 to 1.09, 8 studies, n=7 755). This observation was based almost entirely upon one large study with 6 800 participants (the DIG study). There was a trend toward a lower death rate due to worsening heart failure (p=0.06) and a significant increase in deaths due to other cardiac causes (p=0.04), possibly due to arrhythmias so, that the overall effect on mortality was neutral. Digitalis therapy was associated with a lower rate of hospitalisation (OR 0.68, 95% CI 0.61 to 0.75; relative risk reduction (RRR) 23.4%, NNT ranging from 13 to 17; 4 studies, n=7 262) and a lower rate of clinical deterioration (OR 0.31, 95% CI 0.21 to 0.43; 12 studies, n=1 234).
The effect of digoxin on mortality is controversial. The Digitalis Investigation Group (DIG) trial, the only large randomized trial of digoxin in heart failure, reported a neutral effect on mortality. Some observational studies have reported increased mortality with digoxin treatment. Further analyses of the DIG trial 2 displayed the inability to control bias in observational treatment comparisons despite extensive statistical adjustments, and suggested that prescription of digoxin is an indicator of disease severity and worse prognosis, which cannot be fully accounted for by covariate adjustments.
According to the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 3, digoxin may be considered in patients with symptomatic heart failure with reduced ejection fraction (HFrEF) in sinus rhythm despite treatment with an angiotensin-converting enzyme inhibitor (or angiotensin receptor-neprilysin inhibitor, ARNI), a beta-blocker and an mineralocorticoid receptor antagonist (MRA), to reduce the risk of hospitalization. The effects of digoxin in patients with HFrEF and atrial fibrillation (AF) have not been studied in RCTs, and the effect of digoxin on the prognosis of patients with AF is controversial. In patients with symptomatic heart failure and AF, digoxin may be useful for the treatment of patients with HFrEF and AF with rapid ventricular rate, when other therapeutic options cannot be pursued.
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