Digitalis Use and the Risk of Breast Cancer: A Systematic Review and Meta-Analysis.

INTRODUCTION: Previous epidemiological studies have indicated an increased risk of breast cancer associated with digitalis medication, though results are inconsistent. We performed this systematic review of available epidemiological studies to clarify the association between digitalis use and the risk of breast cancer. METHODS: A search of studies published through May 2016 in MEDLINE and EMBASE databases was performed, supplemented by manual searches of reference lists. The quality of the included studies was assessed, and relative risks were pooled using both random- and fixed-effect models. RESULTS: Three case-control studies and six cohort studies were identified. Meta-analysis generated a pooled relative risk of 1.35 (95% confidence interval 1.24-1.46) in both fixed- and random-effect models. The heterogeneity test suggested low heterogeneity across studies. The funnel plot suggested no existence of publication bias. Subgroup analysis by study design revealed an increased risk of breast cancer associated with digitalis use from cohort studies only (relative risk = 1.39, 95% confidence interval 1.27-1.52), rather than from case-control studies. Studies with adjustment for tobacco smoking or body mass index generated lower overall estimates than those not adjusted. CONCLUSIONS: Existing epidemiological evidence regarding the association between digitalis use and the risk of breast cancer remains inconclusive and more well-designed studies are still needed.

Why Whip the Starving Horse When There Are Oats for the Starving Myocardium?

Digoxin is the oldest drug for treatment of heart failure still in clinical use. Despite over 200 years of clinical experience with this drug, the optimal serum concentration required for both efficacy and safety remains unknown. It has been suggested that low doses have more favorable effects than higher ones. Cardiac glycosides act on the Na/K-ATPase (NKA). They show an inverted U-shaped dose-response curve with inhibition of pumping at high concentrations while increasing NKA activity at low concentrations. The classical sigmoidal dose-response curve describing an inhibition of the NKA by cardiac glycosides cannot explain this stimulatory effect. Cardiac glycosides are prototypical examples of hormetic substances. Biphasic dose-response curves of cardiac glycosides are also found in their neurohormonal effects. In low concentrations, vagomimetic effects are observed, whereas in high concentrations, sympathomimetic effects dominate. Lipophilic Digitalis glycosides have greater sympathomimetic effects; hydrophilic Strophanthus glycosides have greater vagomimetic effects. For digoxin, as a strong inotrope, there is evidence of only weak modulation of the autonomic nervous system. In ouabain, the modulation of the autonomic nervous system prevails over weak inotropic effects. Vagomimetic and sympatholytic effects characterize the therapeutic effects. In contrast to those of digoxin, the therapeutic effects of ouabain follow exactly the measurable serum concentration. Contrary to common prejudice ouabain is suitable for oral administration. Timely adjustments of dosage to patient therapeutic needs are easy to achieve with orally administered ouabain. Ouabain has the potential to crucially improve our arsenal of heart failure medications. Therefore, a clinical re-evaluation of ouabain is warranted. Randomized double-blind prospective clinical studies with ouabain, which meet today's standards, are worthwhile and necessary.

Dronedarone and digitalis: individually reduced post-repolarization refractoriness enhances life-threatening arrhythmias.

AIMS: Interaction between dronedarone and digitalis has been discussed as a possible cause for increased mortality in the presence of dronedarone observed in the PALLAS trial. The aim of this study was to assess possible proarrhythmic effects of dronedarone in combination with digitalis in an experimental whole heart model. METHODS AND RESULTS: Twenty-six female rabbits underwent chronic oral treatment with dronedarone (50 mg/kg/day for 6 weeks). Twenty-four rabbits received placebo. Heart failure was induced by rapid ventricular pacing. Sham-operated rabbits received a right-ventricular pacing lead but were not paced. Thereafter, hearts were isolated and Langendorff-perfused. Monophasic action potentials and a 12 lead electrocardiogram showed a dose-dependent decrease of QT interval, APD90, effective refractory periods, and postrepolarization refractoriness in control hearts and dronedarone-pretreated hearts after application of ouabain (0.1 and 0.2 µM). After acute application of ouabain, ventricular fibrillation (VF) was inducible by programmed ventricular stimulation in 6 of 12 untreated sham hearts (38 episodes) as compared with 7 of 11 dronedarone-pretreated sham hearts (76 episodes). In untreated failing hearts, 6 of 12 hearts were inducible (47 episodes) as compared with 7 of 15 hearts dronedarone-pretreated failing hearts (93 episodes). CONCLUSION: In this study, ouabain treatment resulted in an increased ventricular vulnerability in chronically dronedarone-pretreated control and failing hearts. Ouabain led to a significant abbreviation of ventricular repolarization. This was more marked in dronedarone-pretreated hearts and resulted in an elevated incidence of VF. This may help to interpret the results of the PALLAS trial.

Digoxin--'a friend or foe'.

The authors report about a patient who was admitted after developing nausea, vomiting, change in vision and lethargy. She was on digoxin 250 mcg once daily among all her other medications in the wake of a recent stroke that was accompanied by atrial fibrillation (AF). Her digitalis levels shortly before and on admission were 3.4 and 2.9 ng/ml, respectively. Her admission rhythm was slowly conducted AF at an average of 35 bpm. After a careful assessment by the cardiology consultant in charge, she received Digibind infusion for a chronic digitalis toxicity with the digoxin immune Fab dose based on the formula recommended in the product literature.(3) A few days observation on the ward ensured that her resting heart rate rose to 65 bpm and that she did not need a pacemaker for a slow AF. Her functional status remained reasonably good as she enjoyed a satisfactory recovery postthrombolysis for her recent stroke.

[Treatment of atrial fibrillation: behavioral, pharmacologic and catheter-based perspectives]. / Therapie des Vorhofflimmerns: Verhaltensorientierte, pharmakologische und katheter-interventionelle Perspektiven.

Atrial fibrillation (AF) is the most common heart rhythm disorder, with increasing prevalence in the aging population. The clinical presentation and evolution of AF can be highly variable. Therefore, treatment of AF can be challenging in some patients. This review summarizes recent developments in both prevention of thromboembolic events and rate/rhythm control highlighting the possibilities of behavioral, pharmacological, and catheter-based perspectives.

Digitalis does not improve left atrial mechanical dysfunction after successful electrical cardioversion of chronic atrial fibrillation.

This study was designed to investigate whether administration of digitalis could improve mechanical function of left atrial appendage (LAA) and left atrium prospectively in patients with atrial stunning. Fifty-four consecutive patients in whom atrial stunning was observed immediately after cardioversion of chronic atrial fibrillation (AF) were randomized into digitalis or control group for 1 week following cardioversion. Transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) were performed prior to, immediately following, 1 day after and 1 week after cardioversion to measure transmitral flow velocity and LAA flow velocity. Electrical cardioversion of AF elicited significantly slower left atrial appendage peak emptying velocity (LAA-PEV) and peak filling velocity (LAA-PFV) immediately following cardioversion in both groups. 1 day post cardioversion, there were no significant differences in transmitral E wave, A wave, E/A ratio, LAA-PEV, LAA-PFV or left atrial appendage ejection fraction (LAA-EF) between digitalis and control groups. 1 week post cardioversion, no significant differences were found in transmitral E wave, A wave, E/A ratio, LAA-PEV, LAA-PFV or LAA-EF between the two groups. The occurrence rates of spontaneous echo contrast were not significantly different between digitalis and control groups one day and one week post cardioversion. In conclusion, digitalis did not improve left atrial and appendage mechanical dysfunction following cardioversion of chronic AF. Digitalis did not prevent the development of spontaneous echo contrast in left atrial chamber and appendage. This may be due to the fact that digitalis aggravates intracellular calcium overload induced by chronic AF and has a negative effect on ventricular rate.

Utilidad de la ecuación MDRD para detectar insuficiencia renal oculta y disminuir el riesgo de sobredosificación digitálica / No disponible

Introducción: la Enfermedad Renal Crónica plantea importantes problemas de sobredosificación digitálica y hace necesario el ajuste de dosis y la valoración de la función renal, que se realiza habitualmente mediante la creatinina sérica. Nuestro objetivo fue valorar las ventajas de la creatinina sérica y de la ecuación MDRD para detectar insuficiencia renal oculta y poder reducir el riesgo de sobredosificación digitálica. Material y métodos: estudio descriptivo transversal durante un año, en el que se analizaron las determinaciones de digoxina desde la base de datos del laboratorio. Se excluyeron pacientes infra dosificados y menores de 18 años. Se emplearon las pruebas chi cuadrado (p <0,05), curvas ROC, así como análisis de regresión logística, mediante el programa SPSS. Resultados: se realizaron 1.228 determinaciones de digoxina a 679 pacientes(273 varones 77 ± 10 años, y 406 mujeres 82 ± 8 años), de los que el14% estaba sobre dosificado (28 varones y 67 mujeres).Se observan diferencias significativas en sobredosificación en los que tienen creatininas elevadas respecto a creatinina normal (31 vs. 10% en varones, 44 vs. 15% en mujeres). Mediante curvas ROC, la mayor eficacia diagnóstica se obtendría envarones, con cifras de MDRD <56 ml/min/1,73 m2, y mujeres MDRD <52 ml/min/1,73 m2. El 68% de varones sobre dosificados tenían descensos de MDRD, frente al 61% con creatininas elevadas; el 81% de las mujeres sobredosificadas tenían descendido MDRD frente al 51% con elevación de creatinina. Conclusiones: cifras de creatinina normales esconden insuficiencias renales que aumentan el riesgo de sobredosificación. Utilizar el descenso de la tasa de filtrado glomerular estimado mediante la ecuación MDRD es mejor que utilizar las cifras decreatinina elevadas para detectar sobredosificación digitálica, por lo que constituye una herramienta muy útil para poder reducir el riesgo de sobredosificación, sobre todo en mujeres (AU)

Introduction: Digoxin overdose is closely related to Chronic Kidney Disease and creatinine dosage adjustment is usually needed. Our goal was to assess the advantages of serum creatinine and the MDRD equation to detect hidden renal insufficiency to reduce the overdose Digital risk. Methods: We describe all digoxin samples processed and registered in our hospital laboratory database for a year. Patients under 18 years and samples bellow therapeutic ranges were excluded. Chi square (p<0.05), ROC curves and logistic regression analysis were conducted. SPSS software was used. Results: Between 1228 digoxin samples taken to 679 patients (273 men, 77 ± 10 years old , and 406 women 82 ± 8 years old), 14% were over therapeutic range (28 men and 67 women). Significant differences were observed in over dosage between high creatinine group regarding to normal creatinine group (31% vs. 10% in men, 44% vs. 15% in women). ROC curves showed that the most accurate levels to predict digoxin over dosage were MDRD <56 ml/min/1.73m2 in men and MDRD <52 ml/min/1.73m2 in women. 68% of over dosage men had declines of MDRD levels, compared to 61% with high creatinine levels, 81% of over dosage women had declines of MDRD compared to 51% with elevated creatinine levels. Conclusions: Even in patients with normal creatinine levels, chronic kidney disease enhances digoxin over dose risk. Using the decline of glomerular filtration rate estimated by the MDRD equation is better than elevated creatinine levels to detect digoxin overdose, thus constituting a very useful tool to reduce the risk of overdose, especially among women (AU)

[Analysis of hospital admissions associated with digitalis glycosides]. / Fingerhut--ein alter Hut?: Eine Analyse stationärer Aufnahmen durch digitalisassoziierte unerwünschte Arzneimittelwirkungen.

BACKGROUND: Although the value of digitalis glycosides in the treatment of heart failure is limited, approximately 255 million DDDs of digitalis glycosides (DGs) were prescribed in Germany in 2004. METHOD: The authors analyzed data from adverse drug reactions (ADRs) resulting in hospitalization in the four German Pharmacovigilance Centers (PVCs) associated with DGs between 2000 and 2004. All patients with an at least "probable" ADR were included. RESULTS: Out of 3,092 ADR patients, in 314 patients (10.2%, 244 women) admission was caused by a DG-related ADR. Patients with DG-related ADR had a significantly lower body weight and were significantly older than patients with other ADRs. Per 1,000 patients exposed to DGs the incidence [95% CI] was calculated to 1.9 [1.0; 3.3] ADRs per 3 months exposition. Oral digitoxin was involved in 296 patients (228 women). 70.6% of women but only 29.3% of men were overdosed (> 1 mug/kg body weight per day). Women received significantly higher body weight-related digitoxin doses and had significantly higher digitoxin plasma levels than men. ADRs in patients with nonelevated digitoxin serum level were mainly caused by pharmacodynamic drug-drug interactions (e.g., beta-blockers). Overall, 42.4% of the ADRs were supposed to be preventable. CONCLUSION: Body weight-adapted dosing of digitoxin is essential for preventing DG-ADRs, particularly in elderly women with low body weight. Beyond giving attention to pharmacodynamic and pharmakokinetic drug-drug interactions, regular measurements of digitoxin plasma concentrations are crucial accounting for the increased half-life of digitoxin in the very old.

[Digitalis intoxication secondary to treatment with clarithromycin]. / Original Breve Intoxicación digitálica secundaria al tratamiento con claritromicina.

OBJECTIVE: The goal of this study was to investigate the percentage of patients concurrently receiving digoxin and clarithromycin who exhibited serum digoxin concentrations above the therapeutic range because of a likely interaction between both drugs, and whether digitalis intoxication ensued. METHOD: A descriptive, retrospective study carried out from January 2002 to December 2003 in all inpatients concurrently receiving digoxin and clarithromycin whose serum digoxin concentrations were monitored by the Pharmacy Department s Pharmacokinetics Section. RESULTS: Twenty-six patients having received digoxin and clarithromycin concurrently during their hospital stay were included in the study. Of these, 12 patients (46.2%) had serum digoxin concentrations above the therapeutic range: 7 received digoxin in doses unsuited for their age and/or renal function, and 2 fell short of the mean period of time considered adequate for an interaction to occur. Therefore, only 3 patients had serum digoxin concentrations above the therapeutic range, probably because of an interaction with clarithromycin, and all three had digitalis intoxication symptoms. CONCLUSIONS: According to the results of our study, 11.5% of patients concurrently receiving digoxin and clarithromycin had serum digoxin concentrations above the therapeutic range because of a likely interaction between these two drugs, with digitalis intoxication ensuing. Thus, we deem it necessary to monitor serum digoxin concentrations in patients receiving clarithtomycin.

Intrapericardial drug delivery: pharmacologic properties and long-term safety in swine.

BACKGROUND: Intrapericardial drug delivery is a promising new technique, but the pharmacologic properties of various agents delivered via this route are not known. Furthermore, the long-term safety of intrapericardial catheters has not been previously examined. METHODS: Using a pericardial access device, a catheter connected to a drug-delivery system was implanted in five pigs. Plasma levels and electrocardiographic measurements were obtained after intravenous and intrapericardial administration of digoxin and procainamide. Histological examination was performed after the device had been implanted for a total of 6 months. RESULTS: The QTc interval did not change significantly after digoxin or procainamide intravenous administration. QTc decreased by 47+/-23 ms (p=0.046) 8 h after digoxin intrapericardial administration and increased by 128+/-60 ms (p=0.002) 1 h after procainamide intrapericardial administration. The QRS duration did not change significantly after intravenous administration of either agent, but it increased by 17+/-9 ms (p=0.004) 1 h and by 15+/-4 ms (p=0.01) 8 h after procainamide intrapericardial administration. After intravenous procainamide the RR interval decreased, but it did not change significantly after intrapericardial administration of either agent. Histology showed moderate inflammatory infiltration and fibrosis adjacent to the catheter. CONCLUSIONS: Intrapericardial delivery of digitalis and procainamide produces unique electrophysiological properties. In contrast to satisfactory success of the implantation technique, long-term dwell of the catheter in the pericardium induces moderate, albeit probably clinically significant, fibrosis.

Comparison of digitalis-related adverse events in hospitalized men and women in Italy: an observational study.

BACKGROUND: A higher mortality rate in women than in men treated with digitalis has been described. We hypothesized that this result could be due in part to an increased susceptibility of women to adverse events (AEs) from digitalis. OBJECTIVE: The aim of this study was to compare the incidence of AEs related to digitalis in women and men. METHODS: This was an observational study conducted in geriatrics and internal medicine acute-care wards located throughout Italy. We used the data of the Gruppo Italiano di Farmacoepidemiologia nell'Anziano (Italian Group of Pharmacoepidemiology in the Elderly), a collaborative study group on drug use and adverse drug reactions in hospitalized adults that performed 6 different surveys between 1988 and 1998. Adults who were taking digitalis at the time of admission or during the hospital stay were studied, with no other inclusion or exclusion criteria. The proportion of AEs to digitalis diagnosed at the time of admission or during the hospital stay was compared in men and women. Information on AEs was collected using a structured questionnaire at admission and during the hospital stay. A logistic regression model was used to evaluate the association between sex and AE(s) to digitalis, corrected for potential confounding variables. RESULTS: The total sample size was 9626 patients. Women received a higher weight-adjusted dose of digitalis compared with men (0.0027 mg/kg per day vs 0.0025 mg/kg per day; P < 0.001). Overall, 199 AEs to digitalis were diagnosed. Women were more likely than men to suffer from an AE to digitalis (odds ratio, 1.51; 95% CI, 1.12-2.02). This finding was confirmed after correction for dose of digitalis, age, physical and cognitive impairment, atrial fibrillation, chronic obstructive pulmonary disease, glomerular filtration rate, and use of amiodarone, beta-blockers, nondihydropyridine calcium channel blockers, and potassium-sparing diuretics (odds ratio, 1.58; 95% CI, 1.01-2.48). CONCLUSIONS: In this sample of hospitalized adults in Italy, we found a higher incidence of AEs to digitalis in women than in men.

Consistency of the beneficial effect of metoprolol succinate extended release across a wide range dose of angiotensin-converting enzyme inhibitors and digitalis.

BACKGROUND: The effects of beta-blockade with different extent of angiotensin-converting enzyme inhibitors (ACEI) and digitalization are unknown. To assess the effect of metoprolol succinate controlled release/extended release (CR/XL) combined with high versus low doses of ACEI and digitalis, we analyzed data from The Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF) in which patients with heart failure and left ventricular ejection fraction < or =40% were randomized to metoprolol CR/XL versus placebo. METHODS AND RESULTS: Outcome was analyzed separately for those on a low dose (< or =median) of the ACEI or digitalis versus high dose (> median). The mean dose of ACEI in the high-dose group (n = 1457) was 3 times higher than that in the low-dose group (n = 2094). Mortality was reduced to a similar extent in the high- and low-dose ACEI subgroups (RR = .69 versus .64, respectively). Corresponding figures for combined mortality/all hospitalization and for mortality/hospitalization for heart failure were .85 versus .83, and .70 versus .68, respectively. Likewise, reduction in total mortality with metoprolol CR/XL was similar in patients receiving no digitalis (n = 1447; RR = .56), low dose (n = 1122; RR = .71), or high dose (n = 1421; RR = .71). CONCLUSION: This analysis of MERIT-HF demonstrates consistent and similar improvement in outcome of patients receiving metoprolol CR/XL when combined with either a high or low dose of an ACEI or digitalis, or no digitalis at all. Thus regardless of ACEI and digitalis dose and whether patients are treated with digitalis or not, it is very important to add a beta-blocker to the existing heart failure therapy. beta-blockers should not be withheld until target doses of ACEI have been achieved.