Our findings do not support the hypothesis that digoxin might have a protective effect against progressive renal dysfunction in patients with heart failure. We found that renal function declined with time in the whole cohort but that the rate of decline was significantly faster in patients who were already taking digoxin at baseline. Renal function declines with age,, and more rapidly in patients with heart failure.11 Treatment of heart failure with ACEi and MRAs almost inevitably lead to a degree renal dysfunction, in part due to haemodynamic changes.11,
Digoxin has been used in patients with heart failure for over 200 years, but there is no clear evidence of a benefit on mortality. In the DIG trial, conducted in patients with heart failure due to left ventricular systolic dysfunction who were in sinus rhythm, digoxin reduced hospitalizations due to heart failure by 7.9% but had no significant effect on all-cause mortality.3 In a subgroup analysis, patients with more severe symptoms and signs (NYHA class III/IV or left ventricular ejection fraction less than 25% or who had a cardiothoracic ratio more than 55%) digoxin use was associated with a reduction in 2 year heart failure mortality and hospitalization.3 In contrast, meta-analyses by Vamos and colleagues and Bavishi and colleagues suggested that digoxin was associated with an increase in mortality both in patients with HF and in patients with AF by 21% and 15%, respectively: however, these meta-analyses were conducted on observational and registry studies.3,. Digoxin had no effect on mortality in a meta-analysis of 7 randomised control trials with a control arm in both patients with HF and those with AF. As a consequence of the lack in mortality benefit, digoxin tends to be reserved particularly for those who remain symptomatic despite first line treatment with ACEi, BB and MRA.2
The effect of worsening renal function on digoxin toxicity is well known. In end-stage renal disease, the fluctuating concentration of potassium during dialysis may increase the risk of digoxin toxicity. In patients with end stage renal failure, mortality increases with increasing serum digoxin levels.
Whether digoxin affects renal function is not fully understood. We found that patients on digoxin had a significantly faster rate of decline in eGFR. However, in subgroup analysis of patients in the DIG trial who had their creatinine measured at one year, renal function improved more in patients in the digoxin group than in those taking placebo. Mortality in DIG did not vary with the use of digoxin in relation to renal function, although lower doses of digoxin were prescribed to patients with the lowest estimated glomerular filtration rate (eGFR), presumably as a result of dose adjustment for renal function.
Digoxin is a negatively chronotropic and positively inotropic agent. It inhibits the Na+/K+-ATPase resulting in an increase in intracellular sodium and calcium ions leading to its positive inotropic effect. The negatively chronotropic effect is via an incompletely understood vagotonic effect. Apart from its cardiac uses, cardiac glycosides have been implicated in the regulation of many other physiological and pathophysiological processes. The cardiac glycoside, neriifolin, reduces cerebral infarct size in rodent cerebral hypoxia–ischemia models. Digitalis blocks cell proliferation and non-toxic doses of digitalis can induce apoptosis in different malignant cell lines. Digoxin might thus be useful in diseases associated with autotic cell death or autophagy in the kidneys.4,
Cardiotonic steroids are endogenous ligands of the Na+/K+-ATPase and are implicated in the regulation of natriuresis and vascular tone.,, There is an increased circulating level of the cardiotonic steroid, ouabain, in patients with severely impaired left ventricular function, which has been shown to predict progression of heart failure both in patients with idiopathic dilated cardiomyopathy and in those with left ventricular hypertrophy in end stage renal failure. , In partially nephrectomized rats, diastolic dysfunction and cardiac fibrosis are accompanied by raised levels of cardio tonic steroids. Cardiotonic steroids such as ouabain, digoxin, marinobufagenin and telocinobufagin have all been found to be raised in the plasma of experimental animals and patients with CKD. A four week infusion of the cardiotonic steroid, marinobufagenin induce renal fibrosis in rats. Serum from patients with chronic renal failure and diastolic dysfunction caused inhibition of Na,K-ATPase purified from dog kidney and impaired recovery of cardiac myocyte calcium concentration as well as impaired relaxation of myocytes isolated from Sprague-Dawley rats.
The use of digoxin in patients with heart failure (where serum levels of digoxin are > 1.2ng/ml) is associated with an 11.8% increase in mortality. However, Komiyama and colleagues reported elevated plasma levels of cardiotonic steroids in patients with end stage renal failure, far in excess of 1.2ng/. Cardiotonic steroids at the concentrations detected in patients and animals with CKD can potentially inhibit cardiac Na+/K+-ATPase enzyme activity. In partially nephrectomized rats, active immunization against the cardiotonic steroid, marinobufagenin, causes a dramatic reduction in cardiac hypertrophy and fibrosis. Adding digoxin to endogenous cardiotonic steroids had a synergistic effect on the inhibition of Na+/K+-ATPase.32
The association between worse renal function and digoxin use may be related to atrial fibrillation. We found a very strong association between atrial fibrillation and digoxin usage. The development of AF is associated with a two fold increase in risk of developing end stage renal disease in patients with chronic kidney disease (CKD), independent of baseline eGFR. Animal data show that AF can cause renal vasoconstriction and decreased renal blood flow and even renal fibrosis or possibly renal micro-infarcts., In 386 patients with AF treated by ablation, patients who were arrhythmia free during the first year had an increase in eGFR whilst those who had recurrence of their arrhythmia had a reduction in eGFR (3 ± 8 ml/min/1.73m2 vs -2 ± 8 ml/min/1.73m2, respectively: P < 0.0001).
An additional reason for the greater decline in renal function associated with the use of digoxin may be, at least in part, because digoxin is more likely to be used in patients with more severe heart failure (atrial fibrillation, higher NTproBNP and those already on diuretics) despite treatment with ACEi, beta blockers and MRA.2