Serum Digoxin Research Articles

Pharmacokinetics and dosing requirements of digoxin in pregnant women treated for fetal supraventricular tachycardia

ABSTRACTBackground: The objective of this study was to characterize the pharmacokinetics (PK) of digoxin in pregnant women and its potential implications for drug dosing.Methods: Serum digoxin concentrations (SDCs) obtained in pregnant women treated for fetal supraventricular tachycardia (SVT) was retrospectively collected. PK analysis was comparatively performed using a two-stage approach (PKS™) and a Population PK approach (NONMEM™). As clinical outcome the fetal heart rate was recorded.Results: A total of 42 SDCs were obtained from 8 women in the 3rd trimester of pregnancy (mean age 33.0 years). The PK parameters estimated by both two-stage (volume of distribution (Vd) = 682.0 L, CV = 47.5%; serum clearance (CL) = 16.1 L/h, CV = 19%) and population approaches (Vd = 731.3 L, CV = 30.5%; CL = 18.7 L/h, CV = 17.8%) are very similar and show a clear trend of increasing drug disposition in the third trimester of pregnancy. An oral loading dose of 0.5 mg/8 h during 24 h followed by a maintenance regimen of 0.5 mg/12 h been recommended to start treatment.Conclusions: Despite the small population, these parameters could be used as a guide to calculate the initial dosage requirements in the third trimester of pregnancy for treating fetal SVT. In addition, maternal SDCs should be routinely monitored for dosage adjustment purposes.

The Evaluation of Serum Digoxin Measurement Frequency In Patients Hospitalized In A University Hospital and Treated with Digoxin

Therapeutic drug monitoring (TDM) for digoxin started nearly 50 years ago. However, inappropriate use of TDM for digoxin is still encountered despite so many years of practice. The aims of the study were to find out the frequency of serum digoxin concentration measurements, the rate of unnecessarily frequent measurements and the reasons for unnecessarily frequent measurements. This is a descriptive and a cross sectional study which evaluates the data of the patients who had been hospitalized between January 2011-December 2015, treated with oral digoxin. Patients who had more than one measurement of serum digoxin concentration were included in the study evaluation. When the time between consecutive measurements was less than 7 days, it was considered an “unnecessary measurement”. Descriptive statistical analysis was performed for serum digoxin measurement frequency, time between consecutive measurements, serum digoxin, potassium and creatinine levels, age, gender, diagnosis and the inpatient department. The chi-square, chi-square for trend and logistic regression analysis were used. We evaluated 2065 hospital admissions for 1621 patients and 11407 serum digoxin measurements. The time between consecutive serum digoxin concentration measurements was 1.9±2.4 days and 96.7% of all measurements were classified as unnecessary. While no correlation between patient age, gender, serum creatinine level and measurement frequency was found, unnecessary measurement frequency was high when potassium levels were within the normal range. Unnecessary measurement frequency increased when serum digoxin level exceeded 2 ng/mL. Unnecessary measurements were often performed in all departments with the highest frequency in coronary care unit and cardiology department. In our study, unnecessary serum digoxin measurement frequency was found to be very high although only one of the appropriateness criteria was evaluated. The findings reveal the need for a continuous medical education on TDM in order to plan a proper treatment and reduce unnecessary costs.

Evaluatıon of Serum Dıgoxın Level ın Dıabetıc Patıents ın a 5 Year Retrospectıve Cohort Study

It has been reported that diabetic conditions may alter the expression of P-glycoprotein (P-gp) or its functional activity, and therefore affecting the pharmacokinetic properties of drugs which are P-gp substrates. The aim of this study was to investigate whether the serum level of digoxin, a P-gp subtype, is different in diabetic patients by controlling the effect of other covariate variables. This is a retrospective cohort study evaluating the data measured in the first day of admission to the hospital of patients treated with oral digoxin, who were hospitalized in a university hospital between January 2011 and December 2015. General linear model (GLM) was used for analysis. In this model, digoxin level is dependent variable and diabetes mellitus is fix factor, while age, gender, BUN, creatinine and potassium levels are covariate. P <0.05 was accepted as statistical significant. In this study, total number of hospitalizations was 2974 and DM ratio was 10.7% (n=319). The mean age was 73.1 ± 13.0. The serum digoxin concentration in diabetic patients was calculated as 0.9 ± 0.8 ng/mL (0-4.7ng/mL), and 1.01 ± 1.0 ng/mL (0-15ng/mL) in the non-diabetic patients. In GLM analysis, in the presence of diabetes it was found that digoxin levels decreased significantly (p = 0.016) and other covariate variables such as age, gender, potassium, creatinine and BUN significantly affected the serum digoxin level (P values are p=0.004, p<0.001, p<0.001, p=0.002, p=0.012, respectively). We found that serum digoxin levels decreased in the presence of diabetes. However, further research is needed to determine whether low serum levels of digoxin in diabetic patients are associated with an increase in P-gp expression due to diabetic conditions.

Fatal cardiac glycoside poisoning due to mistaking foxglove for comfrey

Context: Accidental ingestion of foxglove (Digitalis purpurea) can cause significant cardiac toxicity. We report a patient who ingested foxglove mistaking it for comfrey and developed refractory ventricular arrhythmias. The patient died despite treatment with digoxin-specific antibody fragments (DSFab) and veno-arterial extracorporeal membrane oxygenation (VA-ECMO).Case details: A 55-year-old woman presented to the emergency department with nausea, vomiting and generalized weakness eight hours after drinking “comfrey” tea. She had bradycardia (54 beats/min) and hyperkalemia (7.6 mEq/L). Electrocardiogram revealed a first-degree atrioventricular conduction block with premature atrial contractions, followed by polymorphic ventricular tachycardia three hours after arrival. A serum digoxin level was 151.2 ng/mL. The patient developed ventricular fibrillation while waiting for Digibind infusion. Resuscitation was performed and an emergent VA-ECMO was set up. A total of eight vials of Digibind were given over the next 16 hours. She temporarily regained consciousness, but remained hemodynamically unstable and subsequently developed lower limb ischemia and multiple organ failure, and she expired on hospital day seven. A botanist confirmed that the plant was foxglove.Conclusions: The diagnosis of cardiac glycoside plant poisoning can be difficult in the absence of an accurate exposure history. In facilities where DSFab is unavailable or insufficient, early VA-ECMO might be considered in severely cardiotoxic patients unresponsive to conventional therapy.

ABCB1 and SLCO1B3 Gene Polymorphisms and Their Impact on Digoxin Pharmacokinetics in Atrial Fibrillation Patients among the Tunisian Population

Background: Digoxin is a substrate of P-glycoprotein (P-gp) and organic anion transporting polypeptide transporters that are encoded by ABCB1 and SLCO1B3 genes. Genetic polymorphisms in both genes may explain inter-individual variability of serum digoxin concentration (SDC). This study evaluates the possible effect of the most common ABCB1 and SLCO1B3 polymorphisms on SDC after a single oral dose of digoxin in Tunisian atrial fibrillation (AF) patients. Methods:ABCB1 and SLCO1B3 genotypes were analyzed in 102 patients with AF who received digoxin (0.5 mg) without (group I, n = 58) or with the co-administration of P-gp inhibitors (group II, n = 44). SDCs were determined at 6 h following the oral dose. Results: SDCs levels were significantly higher in patients who were co-administered P-gp inhibitors. No influence was noted in ABCB1 and SLCO1B3 polymorphisms on SDC in group I patients. However, SDCs values were significantly different among ABCB1 single nucleotide polymorphisms (SNPs) genotypes of 2677G>T/A (TT, GG>GT, p < 0.05) and 3435C>T (TT, CC>CT, p < 0.05) only in group II with no effect of 1236C>T and SLCO1B3 SNPs. Conclusion: Results suggest that P-gp inhibitors and ABCB1 gene polymorphisms may affect digoxin pharmacokinetics.

Dose response characterization of the association of serum digoxin concentration with mortality outcomes in the Digitalis Investigation Group trial.

Many patients with heart failure and reduced EF remain at high risk for hospitalization despite evidence-based therapy. Digoxin may decrease hospitalization; however, uncertainty persists concerning its proper administration and effect on mortality. This study investigated whether using dose response concepts to re-evaluate the relationship between serum digoxin concentration and key mortality outcomes in patients with reduced EF in the Digitalis Investigation Group trial would help clarify efficacy and safety. Multivariable Cox proportional hazards modelling and propensity score adjustment assessed the relationship between serum digoxin concentration (≥0.5 ng/mL) as a continuous variable and mortality outcomes. In patients treated with digoxin, a significant linear association was found between serum concentration and all-cause mortality [adjusted hazard ratio (HR) 1.25, 95% confidence interval (CI) 1.14-1.38, P < 0.001 per 0.5 ng/mL increase in serum concentration]. Based on this relationship, a bidirectional association was found between digoxin therapy and all-cause mortality when compared with placebo. The lowest serum concentrations (0.5-0.7 ng/mL) were associated with the lowest risk of all-cause mortality (adjusted HR 0.77, 95% CI 0.67-0.89, P < 0.001) while high serum concentrations (1.6-2.0 ng/mL) were associated with increased mortality (adjusted HR 1.33, 95% CI 1.12-1.58, P = 0.001). Consistent with this finding, lower serum concentrations (0.5-0.7 ng/mL) were associated with reduced death from worsening heart failure and a neutral effect on cardiovascular death not due to worsening heart failure. These findings favour targeting serum concentrations from 0.5 to 0.7 ng/mL when dosing digoxin in patients with heart failure and reduced EF.

Evidence Based Digoxin Therapeutic Monitoring - A Lower and Narrower Therapeutic Range

Cardiac glycosides have been used for congestive heart failure and certain cardiac arrhythmias for more than 200 years. Despite the introduction of a variety of new classes of drugs for the management of heart failure, specifically angiotensin-converting enzyme (ACE) inhibitors, b-adrenergic antagonists (bblockers), and the aldosterone antagonist spironolactone, digoxin continues to have an important role in long-term outpatient management. However, a narrow margin exists between therapeutic and toxic doses of digoxin, resulting in a high incidence of digoxin toxicity in clinical practice. A wide variety of placebo-controlled clinical trials have unequivocally shown that treatment with digoxin can improve symptoms, quality of life, and exercise tolerance in patients with mild, moderate, or severe heart failure. The clinical relevance of digoxin therapeutic monitoring is also proved but the SDC (Serum Digoxin Conentrations) required for optimal clinical efficacy and acceptable toxicity remains controversial. In the last years, international guidelines recommend 1.2 ng/mL as acceptable high level. In this bibliographic synthesis, we aim to collect pertinent informations from MedLine database about exposure-effect relationship in order to assess the evidence level scientific of new digoxin therapeutic monitoring

A pharmacokinetic study of digoxin holiday dosing practice in Egypt: A prospective-randomized trial

BackgroundBecause of the narrow therapeutic index of digoxin, most cardiologists in Egypt give digoxin holiday for atrial fibrillation and heart failure, it is not clear if the interrupted digoxin regimens are effective since serum digoxin concentrations might fall below the therapeutic range. ObjectiveTo evaluate and compare the digoxin serum concentration and patient’s quality of life in the continuous versus interrupted digoxin dosing regimens. MethodsPatients were randomized to receive one of four regimens: regimen 1: 0.25mg daily except Friday (N=17); regimen 2: 0.25mg daily except Thursday and Friday (N=17); regimen 3: 0.125mg daily (N=17); and regimen 4: a tailored dose was calculated based on renal function and given daily (N=23). After reaching steady state in the two holiday regimens, two plasma samples were collected (preholiday and post holiday trough concentrations); in the other two groups one trough plasma sample was collected. Quality of life questionnaire for atrial fibrillation (QLAF), was administered to all patients at baseline and then after at least one month of digoxin therapy. ResultsThere was a statistically significant difference between the preholiday trough concentration and the trough steady state concentration across the four regimens (p=0.002). There was no significant difference in the QLAF questionnaire domains, total scores at baseline, or after the follow up between the four regimens. ConclusionOnce daily tablet (0.25mg) was suitable in maintaining digoxin serum concentration in the recommended therapeutic range, fluctuation in digoxin serum concentration did not affect quality of life for atrial fibrillation patients.

Retrospective evaluation of patients with elevated digoxin levels at an emergency department

ObjectivesWe investigated the demographic characteristics, clinical and laboratory findings, treatment strategies and clinical outcomes of patients presenting at emergency department (ED) with digoxin levels at or above 1.2 ng/ml. Materials and methodsThe demographic and clinical characteristics of patients with serum digoxin levels at or above 1.2 ng/ml admitted to an ED between January 2010 and July 2011 were investigated in this cross-sectional descriptive study. Patients with ECG and clinical findings consistent with digoxin toxicity and no additional explanation of their symptoms were evaluated for digoxin toxicity. ResultsIn this study 137 patients were included, and 68.6% of patients were women with mean age 76.1 ± 12.2. There was no significant difference between gender and digoxin intoxication. The mean age of intoxicated group was significantly higher than the non-intoxicated group (P = 0.03). The most common comorbidities were congestive heart failure (n = 91) and atrial fibrillation (n = 74). The most common symptoms were nausea, vomiting and abdominal pain. The levels of hospitalization and mortality in this group were significantly higher. ConclusionDigoxin intoxication must be suspected in patients present in the ED, particularly those with complaints that include nausea and vomiting, as well as new ECG changes; serum digoxin levels must be determined.

Management of digoxin toxicity.

Digoxin toxicity can emerge during long-term therapy as well as after an overdose. It can occur even when the serum digoxin concentration is within the therapeutic range. Toxicity causes anorexia, nausea, vomiting and neurological symptoms. It can also trigger fatal arrhythmias. There is a range of indications for using digoxin-specific antibody fragments. The amount ingested and serum digoxin concentration help to determine the dose required, but are not essential. Digoxin-specific antibody fragments are safe and effective in severe toxicity. Monitoring should continue after treatment because of the small risk of rebound toxicity. Restarting therapy should take into account the indication for digoxin and any reasons why the concentration became toxic.

A New Method for Individualized Digoxin Dosing in Elderly Patients.

Digoxin is a frequently prescribed drug in the elderly population. Estimated glomerular filtration rate is widely used to adjust dosages. The HUGE value is a tool for differentiating the presence or absence of chronic kidney disease in elderly patients. We aimed to investigate the usefulness of the HUGE value to predict the initial dose of digoxin in patients aged older than 70 years. We reviewed retrospectively the medical records of patients aged older than 70 years with serum digoxin concentrations (SDCs) monitored over a 6-month period (63 patients). A linear regression relating the patient's SDC, maintenance dose of digoxin and the HUGE value was estimated to generate a dosage equation. This equation was validated retrospectively (33 patients) and prospectively (35 patients) in comparison with two existing methods based on creatinine clearance. An equation (HUGE_DIG) was generated to calculate the initial digoxin dose to reach a specific target SDC. Thus, to achieve a SDC of 0.8 ng/mL: Digoxin (mg/day) = 0.091 - 0.006 x HUGE. After retrospective validation, the calculated digoxin doses with this equation were administered in the prospective phase and we did not observe statistical differences between measured and desired SDCs. Moreover, the predictive performance of our equation was better than that obtained with the compared methods. We offer a new validated digoxin dosing equation for elderly patients. Our results support the need to perform digoxin dosing in elderly people, bearing in mind the changes in renal physiology secondary to ageing and not merely the estimated glomerular filtration rate.

Development of Highly Specific Enzyme Immunoassay for Monitoring Serum Digitoxin Level in Patients

We previously developed radioimmunoassays (RIAs) for digitoxin and digoxin using antisera raised against digitoxin 3’-hemisuccinate-bovine serum albumin and digoxin 3’-hemisuccinate-bovine serum albumin conjugates, respectively. Very recently, we converted the RIA for digoxin to an enzyme immunoassay (EIA) system. Here, we aimed to convert the RIA for digitoxin to an EIA suitable for measuring serum digitoxin level in patients, using digitoxin 3’-hemisuccinate-β-D-galactosidase as an enzyme-labeled antigen. The developed EIA showed a quantification range of 1 to 70 ng/mL and exhibited high specificity for digitoxin, with low cross-reactivity to digitoxin metabolites. Compared with a commercial anti-digitoxin antiserum clinically used to monitor serum digitoxin level in patients, our antiserum showed much higher specificity for intact digitoxin. Intra- and inter-assay variations were less than 10.0% and 8.5%, respectively. Recovery was within the range of 93.7% - 107.5%. Mean digitoxin concentrations measured in serum samples (n = 26) from digitoxin-treated patients by EIA using our new antiserum and the commercial anti-digitoxin antiserum were 11.0 and 13.8 ng/mL, respectively. The present EIA, which is superior to RIA in terms of convenience and disposal of waste materials, is expected to be practically useful for clinical monitoring of intact digitoxin in serum.

Assessment of Digoxin-Specific Fab Fragment Dosages in Digoxin Poisoning.

Digoxin poisoning still remains a common cause of morbidity and mortality. Fortunately, digoxin-specific Fab fragments are commercially available as an antidote. However, these Fab fragments are several thousand dollars per vial. There is a standardized formula to calculate appropriate Fab fragment dosage based on the serum digoxin concentration. This can greatly reduce the amount of Fab fragment administered. There is also an empiric dosing guideline recommending 6-10 vials be given; however, this may result in higher amounts of Fab fragments being administered than required. We performed this study to assess the amounts of digoxin-specific Fab fragments administered in the treatment of digoxin poisonings recorded in a poison control system database from January 1, 2000, to December 31, 2009, in which digoxin serum concentrations were available. This was a retrospective study of 278 patients, 107 with acute poisonings (group A) and 171 following chronic poisoning (group B). In group A, the calculated Fab dose was higher than the calculated dose based on available concentrations in 39 (36%) of group A and 15 (9%) of group B patients. The average wholesale price cost of the excessive dosages ranged from $4818 to as high as $50,589 per patient. Our data suggests that clinician education on digoxin poisoning and the use of the standardized formula to calculate the Fab dose may decrease over utilization and decrease costs associated with the administration of digoxin-specific Fab fragments in the treatment of digoxin poisonings.

Population pharmacokinetics and optimization of the dosing regimen of digoxin in adult patients.

BackgroundThis study aimed to evaluate the population pharmacokinetics of digoxin in Japanese patients and establish a dosage regimen based on the pharmacokinetic data.MethodsWe analyzed 287 serum digoxin samples from 192 individuals by using the nonlinear mixed effects model. We used simulations to optimize the dosage regimen of digoxin to achieve a high likelihood of the target concentration (0.5–0.8 ng/mL).ResultsThe total body clearance (CL/F ([L/h]) was calculated using the following formula: CL/F = (1.21 + 0.0532 × CLcr [(mL/min]) × (1 + 0.787 × AMD), where CLcr is the creatinine clearance and AMD is 0 in the case of concomitant administration of amiodarone and 1 otherwise. To achieve the target concentration (0.5–0.8 ng/mL), the dosage of digoxin was 0.0625 mg/day (CLcr < 35 mL/min and AMD = 0); 0.125 mg/day (CLcr, 35–65 mL/min and AMD = 0); 0.1875 mg/day (CLcr, 65–100 mL/min and AMD = 0); 0.0625 mg/every other day (CLcr < 30 mL/min and AMD = 1); and 0.0625 mg/day (CLcr, 30–85 mL/min and AMD = 1).ConclusionsOur findings suggest that population parameters are useful for evaluating digoxin pharmacokinetics.

Clinical Risk Stratification for Primary Prevention Implantable Cardioverter Defibrillators.

A conceptualized model may be useful for understanding risk stratification of primary prevention implantable cardioverter defibrillators considering the competing risks of appropriate implantable cardioverter defibrillator shock versus mortality. In a prospective, multicenter, population-based cohort with left ventricular ejection fraction ≤35% referred for primary prevention implantable cardioverter defibrillator, we developed dual risk stratification models to determine the competing risks of appropriate defibrillator shock versus mortality using a Fine-Gray subdistribution hazard model. Among 7020 patients referred, 3445 underwent defibrillator implant (79.7% men, median, 66 years [25th, 75th: 58-73]). During 5918 person-years of follow-up, appropriate shock occurred in 204 patients (3.6 shocks/100 person-years) and 292 died (4.9 deaths/100 person-years). Competing risk predictors of appropriate shock included nonsustained ventricular tachycardia, atrial fibrillation, serum creatinine concentration, digoxin or amiodarone use, and QRS duration near 130-ms peak. One-year cumulative incidence of appropriate shock was 0.9% in the lowest risk category, and 1.7%, 2.5%, 4.9%, and 9.3% in low, intermediate, high, and highest risk groups, respectively. Hazard ratios for appropriate shock ranged from 4.04 to 7.79 in the highest 3 deciles (all P≤0.001 versus lowest risk). Cumulative incidence of 1-year death was 0.6%, 1.9%, 3.3%, 6.2%, and 17.7% in lowest, low, intermediate, high, and highest risk groups, respectively. Mortality hazard ratios ranged from 11.48 to 36.22 in the highest 3 deciles (all P<0.001 versus lowest risk). Simultaneous estimation of risks of appropriate shock and mortality can be performed using clinical variables, providing a potential framework for identification of patients who are unlikely to benefit from prophylactic implantable cardioverter defibrillator.

Serum digoxin concentrations and clinical signs and symptoms of digoxin toxicity in the paediatric population.

Serum digoxin levels have limited utility for determining digoxin toxicity in adults. Paediatric data assessing the utility of monitoring serum digoxin concentration are scarce. We sought to determine whether serum digoxin concentrations are associated with signs and symptoms of digoxin toxicity in children. We carried out a retrospective review of patients 2 ng/ml). There were 87 patients who met study criteria (male 46%, mean age 8.4 years). CHD was present in 67.8% and electrocardiograms were performed in 72.4% of the patients. The most common indication for digoxin toxicity was heart failure symptoms (61.5%). Toxic serum digoxin concentrations were present in 6.9% of patients (mean 2.6 ng/ml). Symptoms associated with digoxin toxicity occurred in 48.4%, with nausea/vomiting as the most common symptom (36.4%), followed by tachycardia (29.5%). Compared with those without toxic serum digoxin concentrations, significantly more patients with toxic serum digoxin concentrations were female (p=0.02). The presence of electrocardiogram abnormalities and/or signs and symptoms of digoxin toxicity was not significantly different between patients with and without serum digoxin concentrations (p>0.05). Serum digoxin concentrations in children are not strongly associated with signs and symptoms of digoxin toxicity.

Dronedarone-digoxin interaction in PALLAS: A foxglove connection?

In the Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) study, dronedarone use was associated with an excess risk of stroke, cardiovascular death and hospitalizations. However, an increased level in the serum digoxin level was observed in the dronedarone arm, as it is a potent inhibitor of the P-glycoprotein transport system. The PALLAS subanalysis suggests that digoxin-dronedarone interaction was responsible for the higher arrhythmic death rate observed in the trial. These data are consistent with several other studies that demonstrate the potential hazard of the use of digoxin in heart failure and/or atrial fibrillation. One must consider other safer alternatives before prescribing digoxin in atrial fibrillation patients.

Population Pharmacokinetics and Optimization of the Dosing Regimen of Digoxin in Adult Patients

Background: This study aimed to evaluate the population pharmacokinetics of digoxin in Japanese patients and establish a dosage regimen based on the pharmacokinetic data. Methods: We analyzed 287 serum digoxin samples from 192 individuals by using the nonlinear mixed effects model. We used simulations to optimize the dosage regimen of digoxin to achieve a high likelihood of the target concentration (0.5-0.8 ng/mL). Results: The total body clearance (CL/F ([L/h]) was calculated using the following formula: CL/F=(1.21i¼‹0.0532 × CLcr [(mL/min]) × (1+0.787 × AMD), where CLcr is the creatinine clearance and AMD is 0 in the case of concomitant administration of amiodarone and 1 otherwise. To achieve the target concentration (0.5–0.8 ng/mL), the dosage of digoxin was 0.0625 mg/day (CLcr <35 mL/min and AMD=0); 0.125 mg/day (CLcr, 35–65 mL/min and AMD=0); 0.1875 mg/day (CLcr, 65–100 mL/min and AMD=0); 0.0625 mg/every other day (CLcr <30 mL/min and AMD=1); and 0.0625 mg/day (CLcr, 30–85 mL/min and AMD=1). Conclusion: Our findings suggest that population parameters are useful for evaluating digoxin pharmacokinetics.

Interaction between digoxin and dronedarone in the PALLAS trial.

Elevated serum digoxin concentration can cause toxicity, including death. Dronedarone increases digoxin concentration by P-glycoprotein interaction. In Permanent Atrial Fibrillation Outcome Study Using Dronedarone On Top Of Standard Therapy Trial (PALLAS), dronedarone was associated with both increased cardiovascular death and heart failure in patients with permanent atrial fibrillation. The present analysis examines whether the dronedarone-digoxin interaction might explain these adverse outcomes. Subgroup analysis was performed to compare outcomes of patients on digoxin at baseline or not. In PALLAS, 1619 patients were randomized to dronedarone and 1617 to placebo, of whom 544 (33.6%) and 526 (32.5%) were receiving digoxin, respectively. Median (Q1,Q3) digoxin serum concentration on day 7 was 1.1 (0.7,1.5) ng/mL on dronedarone and 0.7 (0.5,1.1) ng/mL on placebo (P<0.001). Among patients on digoxin, there were 15 (8.6%/year) cardiovascular deaths on dronedarone and 2 (1.2%/year) on placebo (adjusted hazard ratio, 7.31; 95% confidence interval, 1.66-32.20; P=0.009). Among patients not on digoxin, there were 6 cardiovascular deaths on dronedarone (1.7%/year) and 8 on placebo (2.2%/year; adjusted hazard ratio, 0.67; 95% confidence interval, 0.23-1.95; P=0.46; interaction P value 0.01). In patients on digoxin, there were 11 arrhythmic deaths on dronedarone and none on placebo; and in patients not on digoxin, there were 2 arrhythmic deaths on dronedarone and 4 on placebo (P value for interaction 0.002). There was no interaction between baseline digoxin use and the adverse effect of dronedarone on heart failure events. In PALLAS, there was a strong effect of concurrent digoxin use on the adverse effect of dronedarone on cardiovascular death, but not on occurrence of heart failure. http://www.clinicaltrials.gov. Unique identifier: NCT01151137.

Intermittent low-dose digoxin may be effective and safe in patients with chronic heart failure undergoing maintenance hemodialysis.

A low dose of digoxin is known to reduce mortality and hospitalization in patients with heart failure; however, the safety of digoxin in treating patients with heart failure on maintenance hemodialysis remains controversial. The objective of this study was to determine the effectiveness and safety of digoxin at lower doses in patients with heart failure on maintenance hemodialysis using a retrospective cohort study. This study included 67 heart-failure patients on maintenance hemodialysis: Twenty-four patients received intermittent low doses of digoxin (ILDD), 23 patients received continuous low doses of digoxin (CLDD) and the remaining patients were used as a control group without digoxin treatment. The brain natriuretic peptide (BNP) level and serum digoxin concentrations (SDCs) were measured by ELISA and the changes in left ventricular end diastolic diameter (LVEDD), left ventricular ejection fraction (LVEF), cardiac output (CO) and heart rate (HR) were evaluated by two-dimensional echocardiography. The symptoms of digoxin toxicity were monitored in the treated patients. Compared with the control group, LVEDD, BNP and HR decreased significantly between days 0 and 60 in the ILDD and CLDD groups, but LVEF and CO increased between days 0 and 60 in the same groups (all P<0.05). The levels of BNP and the LVEDD, CO, LVEF and HR were not significantly different between the ILDD and CLDD groups (P>0.05). Furthermore, and the mean SDC of the ILDD group was lower than that of the CLDD group. In the ILDD group, no patients had apparent symptoms of toxicity, but four patients developed digoxin toxicity in the CLDD group. In conclusion an intermittent lower dose of digoxin has beneficial effects and clinical safety in hemodialysis patients with congestive heart failure.