Digoxin

Digoxin is a cardiac glycoside that blocks the sodium-potassium ATPase, as a potent inhibitor of chikungunya virus (CHIKV) infection.

In Vitro:Digoxin, a sodium-potassium ATPase inhibitor, has a negative Z score of −26.67, suggesting a function for the sodium-potassium ATPase in CHIKV infection. Relative to DMSO-treated cells, treatment of U-2 OS cells with Digoxin results in a dose-dependent decrease in CHIKV infection with a half-maximal effective concentration (EC50) of 48.8 nM. Digoxin treatment similarly decreases CHIKV infection of primary human synovial fibroblasts (HSFs) and Vero African green monkey kidney cells with EC50s of 43.9 nM and 67.3 nM, respectively. Digoxin treatment significantly diminishes CHIKV infection in these cell types, with EC50s of 16.2 µM in ST2 cells and 23.2 µM in C2C12 cells, values 330 and 475 times the EC50 of Digoxin in U-2 OS cells. Cell viability is only modestly impaired at 24 h posttreatment with 1 µM Digoxin, a dose 20 times the Digoxin EC50 for CHIKV antiviral activity in these cells[1].

References:
[1]. Ashbrook AW, et al. Antagonism of the Sodium-Potassium ATPase Impairs Chikungunya Virus Infection. MBio. 2016 May 24;7(3). pii: e00693-16.

Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth.[Pubmed:19020076]

Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19579-86.

A library of drugs that are in clinical trials or use was screened for inhibitors of hypoxia-inducible factor 1 (HIF-1). Twenty drugs inhibited HIF-1-dependent gene transcription by >88% at a concentration of 0.4 microM. Eleven of these drugs were cardiac glycosides, including Digoxin, ouabain, and proscillaridin A, which inhibited HIF-1alpha protein synthesis and expression of HIF-1 target genes in cancer cells. Digoxin administration increased latency and decreased growth of tumor xenografts, whereas treatment of established tumors resulted in growth arrest within one week. Enforced expression of HIF-1alpha by transfection was not inhibited by Digoxin, and xenografts derived from these cells were resistant to the anti-tumor effects of Digoxin, demonstrating that HIF-1 is a critical target of Digoxin for cancer therapy.

Meta-analysis of digoxin use and risk of mortality in patients with atrial fibrillation.[Pubmed:25660972]

Am J Cardiol. 2015 Apr 1;115(7):901-6.

There is an ongoing debate on the safety of Digoxin use in patients with atrial fibrillation (AF). To address this issue, the investigators assembled a synthesis of the available evidence on the relation between Digoxin and all-cause mortality in patients with AF. PubMed and the Embase database were systematically searched to identify all eligible studies examining the association between Digoxin use and the mortality risk in AF. Overall hazard ratios and 95% confidence intervals were calculated using the random-effects model. Eleven observational studies were identified that met the inclusion criteria, 5 of which additionally used propensity score matching for statistical adjustment. In total, 318,191 patients were followed up for a mean of 2.8 years. Overall, Digoxin use was associated with a 21% increased risk for mortality (hazard ratio 1.21, 95% confidence interval 1.12 to 1.30). Sensitivity analyses found the results to be robust. In the propensity score-matched AF patients, Digoxin use was associated with a 17% greater risk for mortality (hazard ratio 1.17, 95% confidence interval 1.13 to 1.22). When the AF cohort was grouped into patients with and without heart failure, the use of Digoxin was associated with an increase in mortality in patients with and those without heart failure, and no significant heterogeneity was seen between the groups (p >0.10). In conclusion, the results suggest that Digoxin use was associated with a greater risk for mortality in patients with AF, regardless of concomitant heart failure. A well-powered randomized trial is necessary to reveal the true effect of Digoxin.

Digoxin and risk of death in adults with atrial fibrillation: the ATRIA-CVRN study.[Pubmed:25414270]

Circ Arrhythm Electrophysiol. 2015 Feb;8(1):49-58.

BACKGROUND: Digoxin remains commonly used for rate control in atrial fibrillation, but limited data exist supporting this practice and some studies have shown an association with adverse outcomes. We examined the independent association between Digoxin and risks of death and hospitalization in adults with incident atrial fibrillation and no heart failure. METHODS AND RESULTS: We performed a retrospective cohort study of 14,787 age, sex, and high-dimensional propensity score-matched adults with incident atrial fibrillation and no previous heart failure or Digoxin use in the AnTicoagulation and Risk factors In Atrial fibrillation-Cardiovascular Research Network (ATRIA-CVRN) study within Kaiser Permanente Northern and Southern California. We examined the independent association between newly initiated Digoxin and the risks of death and hospitalization using extended Cox regression. During a median 1.17 (interquartile range, 0.49-1.97) years of follow-up among matched patients with atrial fibrillation, incident Digoxin use was associated with higher rates of death (8.3 versus 4.9 per 100 person-years; P<0.001) and hospitalization (60.1 versus 37.2 per 100 person-years; P<0.001). Incident Digoxin use was independently associated with a 71% higher risk of death (hazard ratio, 1.71; 95% confidence interval, 1.52-1.93) and a 63% higher risk of hospitalization (hazard ratio, 1.63; 95% confidence interval, 1.56-1.71). Results were consistent in subgroups of age and sex and when using intent-to-treat or on-treatment analytic approaches. CONCLUSIONS: In adults with atrial fibrillation, Digoxin use was independently associated with higher risks of death and hospitalization. Given other available rate control options, Digoxin should be used with caution in the management of atrial fibrillation.

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).[Pubmed:25749644]

Lancet. 2015 Jun 13;385(9985):2363-70.

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.