ABSTRACT
Objective: Patients with non-medullary thyroid carcinoma (NMTC) that are refractory to radioactive iodine (RAI) have a poor prognosis. Strategies for restoring the ability to take up iodine, so-called redifferentiation, are promising but not suitable for all patients. Preclinical studies, in human cell lines just as in a murine model, have shown that the cardiac glycoside digoxin restored RAI uptake. This prospective single-center open-label study aimed to investigate whether treatment with digoxin could reinduce clinically relevant RAI uptake in patients with metastasized RAI-refractory NMTC. Methods: Eight patients with metastasized RAI-refractory NMTC were included between November 2022 and June 2023. Before treatment, a baseline [123I]NaI scintigraphy was performed. Thereafter, patients were treated with digoxin for 3 weeks. Starting doses depended on age and weight. For safety reasons, the usual therapeutic range was aimed for. After 1 week, the digoxin plasma concentration was measured, and the digoxin dose was adjusted if necessary. After 3 weeks of digoxin treatment, a second [123I]NaI scintigraphy was performed. RAI uptake was compared between the two scintigraphies. Results: Seven patients completed the digoxin treatment and were evaluable. None of the seven patients showed clinically relevant RAI uptake after digoxin treatment. No digoxin-related serious adverse events occurred during this trial. Conclusion: Contrary to results from preclinical trials, in this trial, 3 weeks of digoxin treatment did not reinduce RAI uptake in patients with NMTC. This highlights essential challenges regarding the approach toward optimization of studies aimed to restore the RAI uptake and its therapeutic efficacy through drug repurposing.
Subject(s)
Digoxin , Iodine Radioisotopes , Thyroid Neoplasms , Humans , Digoxin/therapeutic use , Digoxin/pharmacokinetics , Digoxin/pharmacology , Iodine Radioisotopes/therapeutic use , Thyroid Neoplasms/drug therapy , Thyroid Neoplasms/radiotherapy , Thyroid Neoplasms/pathology , Female , Male , Middle Aged , Prospective Studies , Aged , Adult , Radionuclide ImagingABSTRACT
Consumer-grade wearable technology has the potential to support clinical research and patient management. Here, we report results from the RATE-AF trial wearables study, which was designed to compare heart rate in older, multimorbid patients with permanent atrial fibrillation and heart failure who were randomized to treatment with either digoxin or beta-blockers. Heart rate (n = 143,379,796) and physical activity (n = 23,704,307) intervals were obtained from 53 participants (mean age 75.6 years (s.d. 8.4), 40% women) using a wrist-worn wearable linked to a smartphone for 20 weeks. Heart rates in participants treated with digoxin versus beta-blockers were not significantly different (regression coefficient 1.22 (95% confidence interval (CI) -2.82 to 5.27; P = 0.55); adjusted 0.66 (95% CI -3.45 to 4.77; P = 0.75)). No difference in heart rate was observed between the two groups of patients after accounting for physical activity (P = 0.74) or patients with high activity levels (≥30,000 steps per week; P = 0.97). Using a convolutional neural network designed to account for missing data, we found that wearable device data could predict New York Heart Association functional class 5 months after baseline assessment similarly to standard clinical measures of electrocardiographic heart rate and 6-minute walk test (F1 score 0.56 (95% CI 0.41 to 0.70) versus 0.55 (95% CI 0.41 to 0.68); P = 0.88 for comparison). The results of this study indicate that digoxin and beta-blockers have equivalent effects on heart rate in atrial fibrillation at rest and on exertion, and suggest that dynamic monitoring of individuals with arrhythmia using wearable technology could be an alternative to in-person assessment. ClinicalTrials.gov identifier: NCT02391337 .
Subject(s)
Adrenergic beta-Antagonists , Atrial Fibrillation , Digoxin , Heart Rate , Wearable Electronic Devices , Humans , Digoxin/therapeutic use , Digoxin/pharmacology , Heart Rate/drug effects , Female , Male , Aged , Atrial Fibrillation/drug therapy , Atrial Fibrillation/physiopathology , Adrenergic beta-Antagonists/therapeutic use , Adrenergic beta-Antagonists/pharmacology , Aged, 80 and over , Heart Failure/drug therapy , Heart Failure/physiopathology , Exercise , SmartphoneABSTRACT
Atrial fibrillation (AF) is common, but there are limited data to guide selection of rate control medications (RCM). Reasons for selection are multivariable, and the impact on outcomes is unknown. We investigated prescribing patterns of RCM among patients with AF. Using a nationwide database, we identified 135,927 patients with AF. We stratified by baseline presence of heart failure with reduced ejection fraction (HFrEF) and examined prescription rates of RCM as a function of clinical variables. We also evaluated associations with clinical outcomes. Beta blockers (BB) were most commonly prescribed (44.6%), then calcium channel blockers (CCB) (14.0%) and digoxin (8.6%). Patients prescribed BB were more likely male (45.6% vs 43.4%, p < 0.0001), patients prescribed CCB were less likely male (12.0% vs 16.3%, p < 0.0001). There were higher rates of HF hospitalization (HFH) among females and those with Medicaid. Randomized trials are needed to define optimal choice of RCM.
Subject(s)
Adrenergic beta-Antagonists , Anti-Arrhythmia Agents , Atrial Fibrillation , Calcium Channel Blockers , Practice Patterns, Physicians' , Humans , Atrial Fibrillation/drug therapy , Atrial Fibrillation/epidemiology , Female , Male , Aged , Practice Patterns, Physicians'/statistics & numerical data , Anti-Arrhythmia Agents/therapeutic use , Adrenergic beta-Antagonists/therapeutic use , United States/epidemiology , Middle Aged , Calcium Channel Blockers/therapeutic use , Digoxin/therapeutic use , Heart Rate/physiology , Heart Rate/drug effects , Heart Failure/epidemiology , Heart Failure/drug therapy , Heart Failure/physiopathology , Treatment Outcome , Hospitalization/statistics & numerical data , Retrospective Studies , Databases, Factual , Aged, 80 and over , Stroke Volume/physiologyABSTRACT
BACKGROUND: Some studies have shown digoxin use to be associated with adverse outcomes, including increased mortality. There are limited data on whether digoxin use is associated with increased risk of ventricular tachycardia/ventricular fibrillation (VT/VF) in heart failure patients with an implantable cardioverter-defibrillator (ICD). OBJECTIVES: This study sought to assess whether digoxin use is associated with increased risk of VT/VF in patients with heart failure with reduced ejection fraction with a primary prevention ICD in landmark clinical trials. METHODS: The study cohort consisted of patients with an ICD or cardiac resynchronization therapy-defibrillator who were enrolled in 4 landmark MADIT trials (Multicenter Automatic Defibrillator Implantation Trials). We employed propensity score quintile stratification for treatment with digoxin as well as additional multivariable adjustment to assess the risk of digoxin vs no-digoxin therapy for the endpoints of first and recurrent VT/VF and all-cause mortality. The proportional hazards regression models for arrhythmia-specific endpoints incorporated adjustments for the competing risk of death. RESULTS: At baseline, 1,155 of 4,499 patients were on digoxin (26%). After propensity score quintile stratification, patients prescribed digoxin were shown to exhibit a statistically significant 48% increased risk of VT/VF (P < 0.001), 42% increased risk of the composite of VT/VF or death (P < 0.001), and a 37% increased risk of all-cause mortality (P = 0.006). Digoxin use was also associated with increased risk of appropriate ICD shocks (HR: 1.91; P < 0.001) and with increased burden of VT/VF events (HR: 1.46; P = 0.001). CONCLUSIONS: Our findings suggests that digoxin use is associated with ventricular tachyarrhythmia and death in heart failure with reduced ejection fraction patients with an ICD.
Subject(s)
Defibrillators, Implantable , Digoxin , Heart Failure , Tachycardia, Ventricular , Humans , Digoxin/therapeutic use , Digoxin/adverse effects , Defibrillators, Implantable/adverse effects , Female , Tachycardia, Ventricular/mortality , Male , Middle Aged , Aged , Heart Failure/mortality , Heart Failure/drug therapy , Propensity Score , Ventricular Fibrillation/mortality , Anti-Arrhythmia Agents/therapeutic use , Anti-Arrhythmia Agents/adverse effects , Cohort Studies , Risk FactorsABSTRACT
Therapeutic drug monitoring (TDM) is a crucial clinical practice that improves pharmacological effectiveness and prevent severe drug-related adverse events. Timely reporting and intervention of critical values during TDM are essential for patient safety. In this study, we retrospectively analyzed the laboratory data to provide an overview of the incidence, distribution pattern and biochemical correlates of critical values during TDM. A total of 19,110 samples were tested for nine drug concentrations between January 1, 2019, and December 31, 2020. Of these, 241 critical values were identified in 165 patients. The most common critical values were vancomycin trough (63.4%), followed by tacrolimus trough (16.9%) and digoxin (15.2%). The primary sources of drug critical values were the department of general intensive care unit (ICU), cardiology, and surgery ICU. At baseline or the time of critical value, significant differences were found between the vancomycin, digoxin, and tacrolimus groups in terms of blood urea nitrogen (BUN), creatinine, N-terminal Pro-B-Type Natriuretic Peptide (NT-proBNP), and lymphocyte percentage, P < 0.05. Therefore, it is important to prioritize and closely monitor drug concentrations to reduce laboratory critical values during TDM.
Subject(s)
Digoxin , Drug Monitoring , Tacrolimus , Vancomycin , Humans , Drug Monitoring/methods , Retrospective Studies , Male , Female , Tacrolimus/therapeutic use , Tacrolimus/blood , Vancomycin/blood , Vancomycin/therapeutic use , Vancomycin/pharmacokinetics , Middle Aged , Aged , Digoxin/blood , Digoxin/therapeutic use , Intensive Care Units , Adult , Creatinine/blood , Blood Urea Nitrogen , Natriuretic Peptide, Brain/bloodABSTRACT
AIMS: Digoxin has been used in the treatment for heart failure for centuries, but the role of this drug in the modern era is controversial. A particular concern is the recent observational findings suggesting an increase in all-cause mortality with digoxin, although such observations suffer from biased results since these studies usually do not provide adequate compensation for the severity of disease. Using a nationwide registry database, we aimed to investigate whether digoxin is associated with 1-year all-cause mortality in patients with heart failure irrespective of phenotype. METHODS: A total of 1014 out of 1054 patients in the registry, of whom 110 patients were on digoxin, were included in the study. Multivariable adjustments were done and propensity scores were calculated for various prognostic indicators, including signs and symptoms of heart failure and functional capacity. Crude mortality, mortality adjusted for covariates, mortality in the propensity score-matched cohort, and Bayesian factors (BFs) were analyzed. RESULTS: Crude 1-year mortality rate did not differ between patients on and off digoxin (17.3% vs 20.1%, log-rank p = 0.46), and digoxin was not related to mortality following multivariable adjustment (hazard ratio 0.87, 95% confidence interval 0.539-1.402, p = 0.57). Similarly, all-cause mortality was similar in 220 propensity-score adjusted patients (17.3% vs 20.0%, log-rank p = 0.55). On Bayesian analyses, there was moderate to strong evidence suggesting a lack of difference between in unmatched cohort (BF10 0.091) and weak-to-moderate evidence in the matched cohort (BF10 0.296). CONCLUSIONS: In this nationwide cohort, we did not find any evidence for an increased 1-year mortality in heart failure patients on digoxin.
Subject(s)
Digoxin , Heart Failure , Registries , Humans , Digoxin/therapeutic use , Heart Failure/mortality , Heart Failure/drug therapy , Female , Male , Aged , Middle Aged , Propensity Score , Cardiotonic Agents/therapeutic use , Bayes Theorem , Aged, 80 and overABSTRACT
Major heart failure (HF) trials remain insufficient in terms of assessing the differences in clinical characteristics, biomarkers, treatment efficacy, and safety because of the under-representation of women. The study aimed to present sex-related disparities in HF management, including differences in demographics, co-morbidities, cardiac biomarkers, prescribed medications, and treatment outcomes. The study utilized anonymized data from the Turkish Ministry of Health's National Electronic Database between January 1, 2016, and December 31, 2022. The cohort analysis included 2,501,231 adult patients with HF. Specific therapeutic combinations were analyzed using a Cox regression model to obtain relative risk reduction for all-cause death. The primary end point was all-cause mortality. In the cohort, 48.7% (n = 1,218,911) were male, whereas 51.3% (n = 1,282,320) were female. Female patients exhibited a higher median age (71 vs 68 years) and manifested higher prevalence of diabetes mellitus, anemia, atrial fibrillation, anxiety, and ischemic stroke. Male patients demonstrated higher rates of previous myocardial infarction, dyslipidemia, chronic obstructive pulmonary disease, and chronic kidney disease. Higher concentrations of natriuretic peptides were observed in female patients. Renin-angiotensin aldosterone inhibitor, ß blockers, mineralocorticoid receptor antagonists, sodium/glucose cotransporter 2 inhibitor (SGLT2i), and ivabradine were more commonly prescribed in male patients, whereas loop diuretics, digoxin, and ferric carboxymaltose were more frequent in female patients. Male patients had higher rates of cardiac resynchronization therapy and implantable cardioverter defibrillator implantation rates. All-cause mortality and hospitalization rates were higher in male patients. Compared with monotherapy, all combinations, including SGLT2i, showed a beneficial effect on all-cause mortality in both female and male patients with HF. In hospitalized patients with HF, the addition of digoxin to renin-angiotensin aldosterone inhibitor, mineralocorticoid receptor antagonists, and ß blockers was superior to monotherapy regarding all-cause mortality in female patients with HF compared with male patients with HF. In conclusion, this study highlights that sex-specific responses to HF medication combinations compared with monotherapy and differences in co-morbidities underscore the importance of tailored management strategies. Digoxin showed a contrasting effect on all-cause mortality between both sexes after hospitalization, whereas SGLT2i exhibited a consistent beneficial effect in both sexes when added to all combinations.
Subject(s)
Heart Failure , Renin , Adult , Humans , Male , Female , Aged , Mineralocorticoid Receptor Antagonists/therapeutic use , Aldosterone , Heart Failure/drug therapy , Heart Failure/epidemiology , Digoxin/therapeutic use , Adrenergic beta-Antagonists/therapeutic use , Stroke Volume , Angiotensins/therapeutic use , Biomarkers , Angiotensin Receptor Antagonists/therapeutic useABSTRACT
BACKGROUND: Medical treatment for heart failure with preserved ejection (HFpEF) and heart failure with mildly reduced ejection fraction (HFmrEF) has weaker evidence compared with reduced ejection fraction, despite recent trials with an angiotensin receptor neprilysin inhibitor (ARNI) and sodium glucose co-transporter 2 inhibitors (SGLT2is). OBJECTIVES: The authors aimed to estimate the aggregate therapeutic benefit of drugs for HFmrEF and HFpEF. METHODS: The authors performed a systematic review of MEDLINE, CENTRAL, and Web of Science for randomized trials including patients with heart failure (HF) and left ventricular ejection fraction (LVEF) >40%, treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (analyzed together as renin-angiotensin system inhibitors [RASi]), beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs), digoxin, ARNI, and SGLT2i. An additive component network meta-analysis was performed. The primary outcome was a composite of cardiovascular (CV) death and first hospitalization for heart failure (HHF); secondary outcomes were CV death, total HHF, and all-cause mortality. RESULTS: The authors identified 13 studies with a total of 29,875 patients and a mean LVEF of 56.3% ± 8.7%. ARNI, MRA, and SGLT2i separately, but not RASi, BB, or digoxin, reduced the primary composite outcome compared with placebo. The combination of ARNI, BB, MRA, and SGLT2i was the most effective (HR: 0.47 [95% CI: 0.31-0.70]); this was largely explained by the triple combination of ARNI, MRA, and SGLT2i (HR: 0.56 [95% CI 0.43-0.71]). Results were similar for CV death (HR: 0.63 [95% CI 0.43-0.91] for ARNI, MRA, and SGLT2i) or total HHF (HR: 0.49 [95% CI 0.33-0.71] for ARNI, MRA, and SGLT2i) alone. In a subgroup analysis, only SGLT2i had a consistent benefit among all LVEF subgroups, whereas the triple combination had the greatest benefit in HFmrEF, robust benefit in patients with LVEF 50% to 59%, and a statistically marginal benefit in patients with LVEF ≥60%. CONCLUSIONS: In patients with HF and LVEF>40%, the quadruple combination of ARNI, BB, MRA, and SGLT2i provides the largest reduction in the risk of CV death and HHF; driven by the robust effect of the triple combination of ARNI, MRA, and SGLT2i. The benefit was more pronounced in HFmrEF patients.
Subject(s)
Heart Failure , Humans , Stroke Volume , Ventricular Function, Left , Network Meta-Analysis , Treatment Outcome , Angiotensin Receptor Antagonists , Digoxin/therapeutic useABSTRACT
BACKGROUND: Atrial flutter is an uncommon arrhythmia that can cause severe morbidity, including heart failure and even death in refractory cases. This study investigated the clinical characteristics, treatment, and long-term outcomes of patients with neonatal atrial flutter and its association with heart failure. METHODS: We retrospectively reviewed atrial flutter cases observed in our center between 1999 and 2021 and analyzed the clinical characteristics, treatment, and recurrence according to the presence of heart failure. RESULTS: The study comprised 15 patients with atrial flutter, with median bodyweight and gestational age of 2.7 kg, 37+4 weeks, respectively. Twelve patients were diagnosed with atrial flutter on the first day of life. The median atrial and ventricular rates were 440/min, 220/min, respectively. Four patients exhibited congestive heart failure. Episodic recurrence was noted in five patients and occurred at a higher rate in patients with congestive heart failure (p = 0.004). Antiarrhythmic drugs for maintenance treatment were administered more often in patients with heart failure (p = 0.011). Initial treatment included direct current cardioversion (n = 9), digoxin (n = 4), and observation (n = 2). Four patients treated with cardioversion experienced recurrence during the neonatal period, and none of those treated with digoxin experienced recurrence. The median follow-up duration was 7 years, during which no atrial flutter recurrence was evident. CONCLUSION: Neonates with congestive heart failure had a higher recurrence of atrial flutter. Direct current cardioversion is the most reliable treatment for neonatal atrial flutter, whereas digoxin may be a viable treatment option in refractory and recurrent cases.
Subject(s)
Atrial Flutter , Heart Failure , Infant, Newborn , Humans , Atrial Flutter/diagnosis , Atrial Flutter/epidemiology , Atrial Flutter/therapy , Retrospective Studies , Digoxin/therapeutic use , Anti-Arrhythmia Agents/therapeutic use , Heart Failure/diagnosis , Heart Failure/epidemiology , Heart Failure/therapyABSTRACT
Objetivos: Analizar los factores relacionados con el uso de digoxina en urgencias en pacientes con insuficiencia cardiaca aguda (ICA) y el impacto pronóstico a corto plazo. Método: Se incluyeron pacientes diagnosticados de ICA en 45 servicios de urgencias españoles sin tratamiento crónico con digoxina, los cuales se dividieron según recibiesen digoxina endovenosa en urgencias o no. Se recogieron 51 variables relativas al paciente o al episodio de descompensación y se investigó el perfil del paciente tratado con digoxina en urgencias. Como variables evolutivas se investigaron la necesidad de ingreso, la estancia en urgencias prolongada (> 24 horas) en dados de alta y la hospitalización prolongada (> 7 días) en ingresados, y la mortalidad intrahospitalaria y a 30 días por cualquier causa. Se analizó si el tratamiento con digoxina se asoció a diferencias evolutivas, de forma cruda y ajustada a las características del paciente y el episodio de ICA. Resultados: Se analizaron 15.549 pacientes (mediana = 83 años, mujeres = 55%), de los que 1.430 (9,2%) fueron tratados con digoxina. La digoxina se utilizó más en mujeres, pacientes jóvenes, en mejor clase funcional de la New York Heart Association (NYHA), pero con descompensaciones más graves y, sobre todo, cuando existía una fibrilación auricular (FA) con respuesta ventricular rápida como desencadenante. Se hospitalizó el 75,4% de pacientes (más frecuente en tratados con digoxina; 81,6% vs 74,8%, p < 0,001), tuvo estancia prolongada en urgencias el 38,3% (52,9% vs 37,2%, p < 0,001), hospitalización prolongada el 48,1% (49,3% vs 47,9%, p = 0,385), mortalidad intrahospitalaria el 7,2% (6,9% vs 7,2%, p = 0,712) y a 30 días el 9,7% (9,3% vs 9,7%, p = 0,625). El modelo ajustado mostró que el uso de digoxina en urgencias sólo se asoció con estancia prolongada en urgencias (OR = 1,883, IC 95% = 1,359-2,608), pero no con la necesidad de ingreso, hospitalización prolongada o mortalidad. (AU)
Objectives: To analyze factors related to the use of digoxin to treat patients with acute heart failure (AHF) in emergency departments (EDs) and the impact of digoxin treatment on short-term outcomes. Methods: We included patients diagnosed with AHF in 45 Spanish EDs. The patients, who were not undergoing long-term treatment for heart failure, were classified according to whether or not they were given intravenous digoxin in the ED. Fifty-one patient or cardiac decompensation episode variables were recorded to profile ED patients treated with digoxin. Outcome variables studied were the need for hospital admission, prolonged stay in the ED (> 24 hours) for discharged patients, prolonged hospitalization (> 7 days) for admitted patients, and all-cause in-hospital or 30-day mortality. The associations between digoxin treatment and the outcomes were studied with odds ratios (ORs) adjusted for patient and AHF episode characteristics. Results: Data for 15 549 patients (median age, 83 years; 55% women) were analyzed; 1430 (9.2%) were treated with digoxin. Digoxin was used more often in women, young patients, and those with better New York Heart Association (NYHA) classifications but more severe cardiac decompensation, especially if the trigger was atrial fibrillation with rapid ventricular response. Admissions were ordered for 75.4% of the patients overall (81.6% of digoxin-treated patients vs 74.8% of nontreated patients; P < .001). The ED stay was prolonged in 38.3% of patients discharged from the ED (52.9% of digoxin-treated patients vs 37.2% of nontreated patients; P < .001). The duration of hospital stay was prolonged in 48.1% (digoxin-treated, 49.3% vs 47.9%; P = .385). In-hospital mortality was 7.2% overall (6.9% vs 7.2%, P= .712), and 30-day mortality was 9.7% (9.3% vs 9.7%, P = .625). ED use of digoxin was associated with a prolonged stay in the department (adjusted OR, 1.883; 95% CI, 1.359-2.608) but not with hospitalization or mortality. (AU)
Subject(s)
Humans , Male , Female , Aged , Aged, 80 and over , Heart Failure/drug therapy , Heart Failure/diagnosis , Digoxin/adverse effects , Digoxin/therapeutic use , Spain , Emergency Service, HospitalABSTRACT
Supraventricular tachyarrhythmia (SVT) is the most common form of fetal tachyarrhythmias. The presentation can vary from ill-defined, non-sustained episodes of tachyarrhythmia to frank non-immune hydrops. The standard of care is transplacental therapy by treating the mother with oral antiarrhythmic drugs, followed by direct fetal therapy in refractory cases. We report a case of primigravida in her late 20s, who presented at 28.1 weeks of gestation with fetal hydrops and SVT. She was initially managed with oral digoxin and flecainide, but due to worsening hydrops, risk of fetal demise and extreme prematurity, further management by direct fetal therapy was given in terms of intramuscular digoxin and intraperitoneal flecainide. Following which, the fetus had a favourable outcome. This case highlights the possible role of direct fetal therapy in refractory cases of SVT.
Subject(s)
Fetal Diseases , Tachycardia, Supraventricular , Pregnancy , Female , Humans , Flecainide/therapeutic use , Fetal Diseases/diagnostic imaging , Fetal Diseases/drug therapy , Tachycardia, Supraventricular/diagnosis , Tachycardia, Supraventricular/drug therapy , Anti-Arrhythmia Agents/therapeutic use , Digoxin/therapeutic use , Hydrops Fetalis/diagnosis , Hydrops Fetalis/etiology , Hydrops Fetalis/drug therapy , Arrhythmias, Cardiac , Tachycardia/drug therapy , FetusABSTRACT
Objetivos Analizar los factores relacionados con el tratamiento crónico inadecuado con digoxina, y si esta inadecuación impacta en la evolución a corto plazo. Método Se incluyeron pacientes diagnosticados de insuficiencia cardiaca aguda (ICA) en tratamiento crónico con digoxina, y se clasificaron como con tratamiento indicado o no indicado, investigándose los factores asociados a este hecho, y si se asociaba a mortalidad intrahospitalaria a 30 días, estancia hospitalaria prolongada (>7 días) y evento adverso combinado (reconsulta a urgencias, hospitalización por ICA o muerte por cualquier causa) durante los 30 días postalta. Resultados Se analizaron 2.366 pacientes en tratamiento crónico con digoxina (mediana=83 años, mujeres=61%): adecuado en 1.373 casos (58,0%), inadecuado en 993 (42,0%). La inadecuación se asoció con mayor edad, menor comorbilidad, menor tratamiento con betabloqueantes e IECA, mejor función ventricular y peor índice de Barthel. La mortalidad intrahospitalaria y a 30 días fue mayor en pacientes con tratamiento inadecuado (9,9 versus 7,6%, p=0,05; y 12,6 versus 9,1%, p<0,001; respectivamente); no hubo diferencias en estancia prolongada (35,7 versus 33,8%) ni en eventos adversos posalta (32,9 versus 31,8%). Ajustando las diferencias basales y del episodio de descompensación, el tratamiento crónico inadecuado con digoxina no se asoció con ningún resultado, con odds ratio de 1,31 (IC 95%: 0,85-2,03) para mortalidad intrahospitalaria, 1,29 (0,74-2,25) para mortalidad a 30 días; 1,07 (0,82-1,40) para estancia prolongada y 0,88 (0,65-1,19) para evento adverso posalta. Conclusión Existe un perfil de paciente que recibe de forma inadecuada tratamiento crónico con digoxina, si bien ello no se asocia con resultados adversos a corto plazo durante los episodios de ICA (AU)
Objectives To analyze the factors related to inadequate chronic treatment with digoxin and whether the inadequacy of treatment has an impact on short-term outcome. Method Patients diagnosed with AHF who were in chronic treatment with digoxin were selected. Digoxin treatment was classified as adequate or inadequate. We investigated factors associated to inadequacy and whether such inadequacy was associated with in-hospital and 30-day mortality, prolonged hospital stay (>7 days) and combined adverse event (re-consultation to the ED or hospitalization for AHF or death from any cause) during the 30 days after discharge. Results We analyzed 2366 patients on chronic digoxin treatment (median age=83 years, women=61%), which was considered adequate in 1373 cases (58.0%) and inadequate in 993 (42.0%). The inadequacy was associated with older age, less comorbidity, less treatment with beta-blockers and reninangiotensin inhibitors, better ventricular function, and worse Barthel index. In-hospital and 30-day mortality was higher in patients with inadequate digoxin treatment (9.9% vs. 7.6%, p=0.05; and 12.6% vs. 9.1%, p<0.001, respectively). No differences were recorded in prolonged stay (35.7% vs. 33.8%) or post-discharge adverse events (32.9% vs. 31.8%). In the model adjusted for baseline and decompensation episode differences, inadequate treatment with digoxin was not significantly associated with any outcome, with an odds ratio of 1.31 (95% CI=0.85-2.03) for in-hospital mortality; 1.29 (0.74-2.25) for 30-day mortality; 1.07 (0.82-1.40) for prolonged stay; and 0.88 (0.65-1.19) for post-discharge adverse event. Conclusion There is a profile of patients with AHF who inadequately receive digoxin, although this inadequateness for chronic digitalis treatment was not associated with short-term adverse outcomes (AU)
Subject(s)
Humans , Male , Female , Aged , Aged, 80 and over , Digoxin/therapeutic use , Cardiotonic Agents/therapeutic use , Heart Failure/drug therapy , Treatment Outcome , Cardiotonic Agents/adverse effects , Acute Disease , PrognosisABSTRACT
Background: Intervertebral disc degeneration (IVDD) is a leading cause of low back pain (LBP). The pathological process of IVDD is associated with inflammatory reactions and extracellular matrix (ECM) disorders. Digoxin is widely used for treating heart failure, and it has been reported to have anti-inflammatory effects. Objective: This study is to investigate the role of digoxin in the pathogenesis of intervertebral disc degeneration as well as the involved molecular mechanism, particularly the potential target protein. Methods: We exploited a rat needle model to investigate digoxin's role in intervertebral disc degeneration in vivo. Safranin O staining was used to measure cartilaginous tissue in the intervertebral disc. The morphological changes of intervertebral discs in animal models were determined by Hematoxylin-Eosin (H&E) staining and the pathological score. Primary nucleus pulposus cells (NP cells) from intervertebral discs of patients and murine were used in the present study. Western-Blotting assay, Real-time PCR assay, immunofluorescence staining, and immunochemistry were used to detect the role of digoxin in anti-TNF-α-induced inflammatory effects in vitro. Transfection of siRNA was used to regulate low-density lipoprotein receptor-related protein 4 (LRP4) expression in NP cells to investigate the potential protein target of digoxin. Results: Digoxin protected against intervertebral disc degeneration in rat needle models. Digoxin was found to exert its disc-protective effects through at least three different pathways by a) suppressing TNF-α-induced inflammation, b) attenuating ECM destruction, c) significantly promoting ECM anabolism. Additionally, LRP4 was found to be the downstream molecule of digoxin in NP cells for anti-inflammation and regulation of ECM metabolism. The knockdown of LRP4 downregulated the protective effect of digoxin in NP cells. Conclusion: These findings suggest that digoxin may be a potential therapeutic agent for intervertebral disc degeneration through anti-catabolism and pro-anabolism. Digoxin might also work as an alternative for other inflammation-related diseases.
Subject(s)
Intervertebral Disc Degeneration , Humans , Rats , Mice , Animals , Intervertebral Disc Degeneration/genetics , NF-kappa B/metabolism , Digoxin/pharmacology , Digoxin/therapeutic use , Tumor Necrosis Factor Inhibitors/therapeutic use , Tumor Necrosis Factor-alpha/metabolism , Inflammation/metabolism , LDL-Receptor Related ProteinsABSTRACT
Neuroinflammation plays an important role in the pathogenesis of epilepsy, so it is necessary to clarify the influence of standard antiepileptic drugs as well as adjuvant agents (e.g., cardiac glycoside digoxin, which previously showed a clear anticonvulsant potential) on cyclooxygenase pathway and neuron-specific enolase under the conditions of chronic epileptogenesis. The aim of the article is to determine the effect of digoxin, sodium valproate, and celecoxib per se, as well as the combination of digoxin with sodium valproate on the content of cyclooxygenase 1 and 2 types, prostaglandins E2, F2α, I2, thromboxane B2, 8-isoprostane and neuron-specific enolase in the brain of mice in the pentylenetetrazole-induced kindling model. It was found that only the combination of sodium valproate with digoxin provides a complete protective effect (absence of seizures) and shows the clearest influence on neuroinflammation markers and neuronal damage than monotherapy with each of these drugs and celecoxib, which appeared to be an ineffective anticonvulsant. The obtained results indicate that digoxin is a promising adjuvant drug to classical antiepileptic drugs (mostly sodium valproate) in epilepsy treatment.c.
Subject(s)
Epilepsy , Valproic Acid , Rats , Mice , Animals , Valproic Acid/pharmacology , Valproic Acid/therapeutic use , Anticonvulsants/pharmacology , Anticonvulsants/therapeutic use , Pentylenetetrazole/pharmacology , Pentylenetetrazole/therapeutic use , Celecoxib/pharmacology , Celecoxib/therapeutic use , Prostaglandin-Endoperoxide Synthases/therapeutic use , Digoxin/therapeutic use , Neuroinflammatory Diseases , Rats, Wistar , Epilepsy/chemically induced , Epilepsy/drug therapy , Phosphopyruvate Hydratase/therapeutic useABSTRACT
Background Digoxin prescription in patients with single-ventricle physiology after stage 1 palliation is associated with reduced interstage death. Prior literature has primarily included patients having undergone the Norwood procedure. We sought to determine if digoxin prescription at discharge in infants following hybrid stage 1 palliation was associated with improved transplant-free interstage survival. Methods and Results A retrospective multicenter cohort analysis was conducted using data from the National Pediatric Cardiology Quality Improvement Collaborative registry data from 2008 to 2021. Infants with functional single ventricles and aortic arch obstruction discharged home after the hybrid stage 1 palliation hospitalization were included. Patients were excluded if they had supraventricular tachycardia or conversion to Norwood operation. The primary outcome was transplant-free survival. Multivariable logistic regression analysis including a propensity score for digoxin use identified associations between digoxin use and interstage death or transplant. Of 259 included infants from 45 sites, 158 (61%) had hypoplastic left heart syndrome. Forty-nine percent had a gestational age ≤38 weeks, 18% had a birth weight <2.5 kg, and 58% had a preoperative risk factor. Of the 259 subjects, 129 (50%) were discharged on digoxin. Interstage death or transplant occurred in 30 (23%) patients in the no-digoxin group compared with 18 (14%) in the digoxin group (P=0.06). With multivariate analysis, discharge digoxin prescription was associated with a lower risk of interstage death or transplant (adjusted odds ratio, 0.48 [95% CI, 0.24-0.93]; P=0.03). Conclusions In infants with single-ventricle physiology who underwent hybrid stage 1 palliation, digoxin prescription at hospital discharge was associated with improved interstage transplant-free survival.
Subject(s)
Hypoplastic Left Heart Syndrome , Norwood Procedures , Univentricular Heart , Humans , Infant , Digoxin/therapeutic use , Heart Ventricles/surgery , Hypoplastic Left Heart Syndrome/surgery , Palliative Care/methods , Retrospective Studies , Risk Factors , Treatment OutcomeABSTRACT
Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1-15), followed by RIF40 (days 16-30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%-115%); tolbutamide, 80% (74%-86%); omeprazole, 55% (47%-65%); dextromethorphan, 77% (68%-86%); midazolam, 62% (49%-78%), and 117% (105%-130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.
Subject(s)
Cytochrome P-450 CYP1A2 , Tuberculosis, Pulmonary , Adult , Humans , Midazolam/therapeutic use , Cytochrome P-450 CYP2D6/metabolism , Caffeine , Rifampin/therapeutic use , Cytochrome P-450 CYP2C19 , Cytochrome P-450 CYP3A/metabolism , Dextromethorphan/therapeutic use , Tolbutamide , Cytochrome P-450 CYP2C9/metabolism , Cytochrome P-450 Enzyme System/metabolism , Omeprazole , Drug Interactions , Tuberculosis, Pulmonary/drug therapy , Digoxin/therapeutic useABSTRACT
OBJECTIVES: To analyze the factors related to inadequate chronic treatment with digoxin and whether the inadequacy of treatment has an impact on short-term outcome. METHOD: Patients diagnosed with AHF who were in chronic treatment with digoxin, were selected. Digoxin treatment was classified as adequate or inadequate. We investigated factors associated to inadequacy and whether such inadequacy was associated with in-hospital and 30-day mortality, prolonged hospital stay (>7 days) and combined adverse event (re-consultation to the ED or hospitalization for AHF or death from any cause) during the 30 days after discharge. RESULTS: We analyzed 2,366 patients on chronic digoxin treatment (median ageâ¯=â¯83 years, womenâ¯=â¯61%), which was considered adequate in 1,373 cases (58.0%) and inadequate in 993 (42.0%). The inadequacy was associated with older age, less comorbidity, less treatment with beta-blockers and renin-angiotensin inhibitors, better ventricular function, and worse Barthel index. In-hospital and 30-day mortality was higher in patients with inadequate digoxin treatment (9.9% versus 7.6%, pâ¯=â¯0.05; and 12.6% versus 9.1%, pâ¯<â¯0.001, respectively). No differences were recorded in prolonged stay (35.7% versus 33.8%) or post-discharge adverse events (32.9% versus 31.8%). In the model adjusted for baseline and decompensation episode differences, inadequate treatment with digoxin was not significantly associated with any outcome, with an odds ratio of 1.31 (95%CIâ¯=â¯0.85-2.03) for in-hospital mortality; 1.29 (0.74-2.25) for 30-day mortality; 1.07 (0.82-1.40) for prolonged stay; and 0.88 (0.65-1.19) for post-discharge adverse event. CONCLUSION: There is a profile of patients with AHF who inadequately receive digoxin, although this inadequateness for chronic digitalis treatment was not associated with short-term adverse outcomes.
Subject(s)
Digoxin , Heart Failure , Humans , Female , Aged, 80 and over , Digoxin/therapeutic use , Aftercare , Patient Discharge , Emergency Service, Hospital , Heart Failure/drug therapy , Prognosis , Acute DiseaseABSTRACT
OBJECTIVES: Randomized controlled trials are the gold-standard for determining therapeutic efficacy, but are often unrepresentative of real-world settings. Statistical transportation methods (hereafter transportation) can partially account for these differences, improving trial applicability without breaking randomization. We transported treatment effects from two heart failure (HF) trials to a HF registry. STUDY DESIGN AND SETTING: Individual-patient-level data from two trials (Carvedilol or Metoprolol European Trial (COMET), comparing carvedilol and metoprolol, and digitalis investigation group trial (DIG), comparing digoxin and placebo) and a Scottish HF registry were obtained. The primary end point for both trials was all-cause mortality; composite outcomes were all-cause mortality or hospitalization for COMET and HF-related death or hospitalization for DIG. We performed transportation using regression-based and inverse odds of sampling weights (IOSW) approaches. RESULTS: Registry patients were older, had poorer renal function and received higher-doses of loop-diuretics than trial participants. For each trial, point estimates were similar for the original and IOSW (e.g., DIG composite outcome: OR 0.75 (0.69, 0.82) vs. 0.73 (0.64, 0.83)). Treatment effect estimates were also similar when examining high-risk (0.64 (0.46, 0.89)) and low-risk registry patients (0.73 (0.61, 0.86)). Similar results were obtained using regression-based transportation. CONCLUSION: Regression-based or IOSW approaches can be used to transport trial effect estimates to patients administrative/registry data, with only moderate reductions in precision.