Simple and safe digitoxin dosing in heart failure based on data from the DIGIT-HF trial.

BACKGROUND: The present study aimed to develop a simple dosing score when starting the cardiac glycoside digitoxin in heart failure with reduced ejection fraction (HFrEF) employing first data from the randomized, double-blinded DIGIT-HF trial. METHODS AND RESULTS: In DIGIT-HF, digitoxin was started with a dose of 0.07 mg once daily (o.d.) in all patients. For score derivation, 317 patients were analyzed who had been randomized to digitoxin. In these patients, after scheduled determination of serum levels at study week 6, the digitoxin dose had remained unchanged or had been reduced to 0.05 mg o.d. (97% of patients) to achieve serum concentrations within a predefined range (10.5-23.6 nmol/l). In logistic regression analyses, sex, age, body mass index (BMI), and estimated glomerular filtration rate (eGFR) were associated with need for dose reduction and, therefore, selected for further developing the dosing score. Optimal cut-points were derived from ROC curve analyses. Finally, female sex, age ≥ 75 years, eGFR < 50 ml/min/1.73 m2, and BMI < 27 kg/m2 each were assigned one point for the digitoxin dosing score. A score of ≥ 1 indicated the need for dose reduction with sensitivity/specificity of 81.6%/49.7%, respectively. Accuracy was confirmed in a validation data set including 64 patients randomized to digitoxin yielding sensitivity/specificity of 87.5%/37.5%, respectively. CONCLUSION: In patients with HFrEF, treatment with digitoxin should be started at 0.05 mg o.d. in subjects with either female sex, eGFR < 50 ml/min/1.73m2, BMI < 27 kg/m2, or age ≥ 75 years. In any other patient, digitoxin may be safely started at 0.07 mg o.d.

Digitalis Therapy and Risk of Recurrent Ventricular Tachyarrhythmias and ICD Therapies in Atrial Fibrillation and Heart Failure.

OBJECTIVE: This study sought to assess the impact of treatment with digitalis on recurrences of ventricular tachyarrhythmias in implantable cardioverter defibrillator (ICD) recipients with atrial fibrillation (AF) and heart failure (HF). BACKGROUND: The data regarding outcomes of digitalis therapy in ICD recipients are limited. METHODS: A large retrospective registry was used, including consecutive ICD recipients with episodes of ventricular tachyarrhythmia between 2002 and 2016. Patients treated with digitalis were compared to patients without digitalis treatment. The primary prognostic outcome was first recurrence of ventricular tachyarrhythmia at 5 years. Kaplan-Meier and multivariable Cox regression analyses were applied. RESULTS: A total of 394 ICD recipients with AF and/or HF was included (26% with digitalis treatment and 74% without). Digitalis treatment was associated with decreased freedom from recurrent ventricular tachy-arrhythmias (HR = 1.423; 95% CI 1.047-1.934; p = 0.023). Accordingly, digitalis treatment was associated with decreased freedom from appropriate ICD therapies (HR = 1.622; 95% CI 1.166-2.256; p = 0.004) and, moreover, higher rates of rehospitalization (38 vs. 21%; p = 0.001) and all-cause mortality (33 vs. 20%; p = 0.011). CONCLUSION: Among ICD recipients suffering from AF and HF, treatment with digitalis was associated with increased rates of recurrent ventricular tachyarrhythmias and ICD therapies. However, the endpoints may also have been driven by interactions between digitalis, AF, and HF.

Overgangen fra digitoksin til digoksin i årene 2011­13.

BACKGROUND: The withdrawal of digitoxin and subsequent substitution with digoxin around 2012 may have led to an increased health risk for patients. The aim of this study was to follow individual patients during the switch. MATERIAL AND METHOD: Serum concentrations of digitoxin and digoxin, measured at the Department of Clinical Pharmacology at St Olavs University Hospital in the period 1 January 2011-31 December 2013 were reviewed. Patients who had switched from digitoxin to digoxin and whose serum concentrations of both drugs had been measured during this period were included. RESULTS: A total of 304 patients, 1686 samples and 1858 serum concentration analyses were included in the study. Therapeutic serum concentrations were measured in 171 patients (56.3 %) before the switch and 176 (57.9 %) after this had taken place. Altogether 108 patients (35.5 %) had therapeutic concentrations both before and after the change. For 58.9 % of the patients, the change resulted in a reduction in serum concentration of digitalis, calculated as digoxin equivalents. The proportion of patients with assumed supratherapeutic concentrations fell from 43.1 % to 33.9 %; however, the proportion of patients with toxic serum concentrations rose from 0.3 % to 3.0 %. INTERPRETATION: Although the switch led to a reduction in dose and serum concentration for many, a significant number of patients may have been put in harm's way.

[Drug safety associated with the change of digitalis drug in Norway]. / Legemiddelsikkerhet ved bytte av digitalispreparat i Norge.

BACKGROUND In 2011, following a period with delivery problems, the only registered digitoxin drug in Norway was replaced with digoxin. As a result, approximately 21 000 patients had to replace digitoxin with digoxin. There are important pharmacokinetic differences between digitoxin and digoxin (the general term for both drugs is digitalis), which must be taken into account when changing therapy. The aim of this study was to investigate compliance of drug security, during the transition from digitoxin to digoxin in Norway.MATERIAL AND METHOD Enquiries addressed to the Norwegian Poison Information Centre and reports of fatal adverse effects to the Regional Drug Information Centres (RELIS) regarding intake of digitalis were analysed. Serum concentrations of digitoxin and digoxin analyzed at Oslo University Hospital were reviewed. All data sources were reviewed for the years 2010-2014 and patients > 20 years were included.RESULTS The total number of enquiries addressed to the Norwegian Poison Information Centre, fatal adverse drug reactions reported to RELIS, and patient samples in the toxic range analyzed at Oslo University Hospital increased from 2012, timewise related to the transition to digoxin.INTERPRETATION Despite extensive information from the Norwegian Medicines Agency, a small, transient increase was observed in the number of overdoses and reported deaths from digitalis related to change in therapy. The cause of the overdose was in many cases unknown. This study revealed several cases of incorrect dosage, simultaneous use of digitoxin and digoxin, and washout time that was insufficient or lacking before initiation of digoxin.

Effects of digitalis on mortality in a large cohort of implantable cardioverter defibrillator recipients: results of a long-term follow-up study in 1020 patients.

AIMS: The effects of digitalis on mortality in patients with structural heart disease are controversially discussed. We aimed to assess the effects of digitalis administration in implantable cardioverter defibrillator (ICD) recipients. METHODS AND RESULTS: This retrospective analysis comprises 1020 consecutive patients who received an ICD at our institution and who were followed for up to 10 years (median 37 months). A total of 438 patients were receiving digitalis at the time of ICD implantation and 582 did not. Patients on digitalis were more often in atrial fibrillation and had more often a prolonged QRS duration of ≥120 ms, a severely impaired left ventricular ejection fraction, and higher New York Heart Association (NYHA) classification heart failure. Crude Kaplan-Meier analysis demonstrated significantly higher mortality in patients on digitalis (HR = 2.47; 95% CI 1.87-3.25; P = 0.001). After adjustment for patient characteristics found statistically significant in adjusted Cox regression analysis (age, gender, NYHA classification, and QRS duration of ≥120 ms), a HR of 1.65 remained (95% CI 1.14-2.39; P = 0.01). Patients on digitalis died more often from cardiac arrhythmic and cardiac non-arrhythmic causes than patients not on digitalis (P = 0.04). There was no difference in mortality between patients receiving digitoxin and those receiving digoxin (HR = 1.55; 95% CI 0.74-3.25; P = 0.25). CONCLUSION: In this large ICD patient population, digitalis use at baseline was independently associated with increased mortality even after careful adjustment for possible confounders. Digitalis should be used with great caution in this population.

Rhabdomyolysis after addition of digitoxin to chronic simvastatin and amiodarone therapy.

Rhabdomyolysis is a well known side effect of statin therapy. Several drugs may increase its risk by drug-drug interactions. In particular, patients with heart disease receive more and more different compounds to cope with all the pathomechanisms involved and may therefore be of high risk for side effects. We report a case of rhabdomyolysis in a patient with heart failure on a multi-drug regimen caused by a drug interaction between chronic statin therapy (simvastatin), amiodarone and newly administrated digitoxin. The patient recovered fully after cessation of simvastatin therapy, the other drugs were given continuously. Potential mechanisms of this event are discussed. Most interesting in this case is that rhabdomyolysis occurred only after starting digitoxin after long-term therapy with the statin.

Nonocclusive mesenteric ischemia induced by digitalis.

BACKGROUND: Nonocclusive mesenteric ischemia is a rare but serious disorder with a high mortality rate; causal factors include cardiac glycosides, digoxin, and digitoxin in addition to severe hypotension, decompensated heart failure, and septic shock. CASE PRESENTATION: We present a patient with digitoxin intoxication who died from autopsy-confirmed ischemic gangrenous colitis. CONCLUSION: Despite the frequent occurrence of intoxication with cardiac glycosides nonocclusive mesenteric ischemia is a rare event. However, it should always be included as a differential diagnosis of diffuse abdominal pain in patients treated with cardiac glycosides.

Digitoxin medication and cancer; case control and internal dose-response studies.

BACKGROUND: Digitoxin induces apoptosis in different human malignant cell lines in vitro. In this paper we investigated if patients taking digitoxin for cardiac disease have a different cancer incidence compared to the general population. METHODS: Computer stored data on digitoxin concentrations in plasma from 9271 patients with cardiac disease were used to define a user population. Age and sex matched controls from the Norwegian Cancer Registry were used to calculate the number of expected cancer cases. RESULTS: The population on digitoxin showed a higher incidence of cancer compared to the control population. However, an additional analysis showed that the population on digitoxin had a general increased risk of cancer already, before the start on digitoxin. Leukemia/lymphoma were the cancer types which stood out with the highest risk in the digitoxin population before starting on digitoxin. This indicates that yet unknown risk factors exist for cardiovascular disease and lymphoproliferative cancer. An internal dose-response analysis revealed a relationship between high plasma concentration of digitoxin and a lower risk for leukemia/lymphoma and for cancer of the kidney/urinary tract. CONCLUSION: Morbidity and mortality are high in the population on digitoxin, due to high age and cardiac disease. These factors disturb efforts to isolate an eventual anticancer effect of digitoxin in this setting. Still, the results may indicate an anticancer effect of digitoxin for leukemia/lymphoma and kidney/urinary tract cancers. Prospective clinical cancer trials have to be done to find out if digitoxin and other cardiac glycosides are useful as anticancer agents.