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BackgroundAtrial fibrillation (AF) is a major and increasing burden on health services. This study aimed to evaluate the cost-effectiveness of digoxin versus beta-blockers for heart rate control in patients with permanent AF and symptoms of heart failure.MethodsRAte control Therapy Evaluation in permanent Atrial Fibrillation (RATE-AF) was a randomised, open-label, blinded, endpoint trial embedded in the UK National Health Service (NHS) to directly compare low-dose digoxin with beta-blockers (ClinicalTrials.gov: NCT02391337). A trial-based cost-utility analysis was performed from a healthcare perspective over 12 months. Resource use in primary and secondary healthcare services, medications and patient-reported quality of life were prospectively collected to estimate differences in costs and quality-adjusted life years (QALYs).ResultsRATE-AF randomised 160 patients with mean age of 76 (SD 8) years and 46% women, of which 149 patients (n=73 digoxin, n=76 beta blockers) had complete data and survived to 12-month follow-up. Treatment with digoxin was significantly less costly, with a mean saving of £530.41 per patient per year (95% CI −£848.06 to −£249.38, p=0.001). This was principally due to substantially lower rates of adverse events, with less primary and secondary healthcare utilisation compared with beta-blocker therapy. There was no significant difference in QALYs (0.013; 95% CI −0.033 to 0.052, p=0.56). At the £20 000 per-QALY willingness to pay threshold, the probability of digoxin being cost-effective compared with beta-blockers was 94%, with potential annual savings to the NHS of £102 million/year (95% CI £48 million to £164 million saving, p=0.001).ConclusionsDigoxin is a less costly option when compared with beta-blockers for control of heart rate in suitable patients with permanent AF, with larger cost-effectiveness studies warranted to advise on national and global policy-making.Trial registration number NCT02391337, EudraCT 2015-005043-13.

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 . In a substudy of the RATE-AF trial, which compared heart rate control therapy using digoxin or the beta-blocker bisoprolol, heart rate and physical activity data collected using a wearable device showed equivalent heart rate control by the two drugs and could be used to predict future heart failure functional class as well as standard clinical measurements.

Patients with permanent atrial fibrillation and additional cardiac risk factors were randomly assigned to receive either dronedarone or placebo. At a median of 3.5 months, the risk of major adverse cardiovascular events was significantly increased with dronedarone. Dronedarone is a new antiarrhythmic agent that is used to restore sinus rhythm and to reduce rates of hospitalization for cardiovascular causes in patients with intermittent (paroxysmal or persistent) atrial fibrillation. 1 In ATHENA (A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg bid for the Prevention of Cardiovascular Hospitalization or Death from any Cause in Patients with Atrial Fibrillation/Atrial Flutter; ClinicalTrials.gov number, NCT00174785), 4628 patients with intermittent atrial fibrillation were randomly assigned to receive either dronedarone or placebo. Dronedarone reduced the incidence of the primary outcome of unplanned hospitalization for cardiovascular causes or death. Significant . . .

Despite numerous examples of the effects of the human gastrointestinal microbiome on drug efficacy and toxicity, there is often an incomplete understanding of the underlying mechanisms. Here, we dissect the inactivation of the cardiac drug digoxin by the gut Actinobacterium Eggerthella lenta. Transcriptional profiling, comparative genomics, and culture-based assays revealed a cytochrome-encoding operon up-regulated by digoxin, inhibited by arginine, absent in nonmetabolizing E. lenta strains, and predictive of digoxin inactivation by the human gut microbiome. Pharmacokinetic studies using gnotobiotic mice revealed that dietary protein reduces the in vivo microbial metabolism of digoxin, with significant changes to drug concentration in the serum and urine. These results emphasize the importance of viewing pharmacology from the perspective of both our human and microbial genomes.

Background and Objective Vandetanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and rearranged during transfection (RET) signalling, indicated for the treatment of medullary thyroid cancer. We investigated potential drug–drug interactions between vandetanib and metformin [organic cation transporter 2 (OCT2) substrate; NCT01551615]; digoxin [P-glycoprotein (P-gp) substrate; NCT01561781]; midazolam [cytochrome P450 (CYP) 3A4 substrate; NCT01544140]; omeprazole (proton pump inhibitor) or ranitidine (histamine H 2 -receptor antagonist; both NCT01539655). Methods Four open-label, phase I studies were conducted in healthy volunteers: n  = 14 (metformin), n  = 14 (digoxin), n  = 17 (midazolam), n  = 16 (omeprazole), n  = 18 (ranitidine). Three of these comprised the following regimens: metformin 1000 mg ± vandetanib 800 mg, midazolam 7.5 mg ± vandetanib 800 mg, or digoxin 0.25 mg ± vandetanib 300 mg. The randomized study comprised vandetanib 300 mg alone and then either (i) omeprazole 40 mg (days 1–4), and omeprazole + vandetanib (day 5); or (ii) ranitidine 150 mg (day 1), and ranitidine + vandetanib (day 2). The primary objective assessed metformin, digoxin, midazolam and vandetanib pharmacokinetics. Results Vandetanib + metformin increased metformin area under the plasma concentration–time curve from zero to infinity (AUC 0–∞ ) and maximum observed plasma concentration (C max ) by 74 and 50 %, respectively, and decreased the geometric mean metformin renal clearance (CL R ) by 52 % versus metformin alone. Vandetanib + digoxin increased digoxin area under the concentration-time curve from zero to the last quantifiable concentration (AUC 0–last ) and C max by 23 and 29 %, respectively, versus digoxin alone, with only a 9 % decrease in CL R . Vandetanib had no effect on midazolam exposure. Vandetanib exposure was unchanged during co-administration with omeprazole/ranitidine. Treatment combinations were generally well tolerated. Conclusion Patients receiving vandetanib with metformin/digoxin may require additional monitoring of metformin/digoxin, with dose adjustments where necessary. Vandetanib with CYP3A4 substrates or omeprazole/ranitidine is unlikely to result in clinically relevant drug–drug interactions.

Digoxin is a widely used drug for ventricular rate control in patients with atrial fibrillation (AF), despite a scarcity of randomised trial data. We studied the use and outcomes of digoxin in patients in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). For this retrospective analysis, we included and classified patients from ROCKET AF on the basis of digoxin use at baseline and during the study. Patients in ROCKET AF were recruited from 45 countries and had AF and risk factors putting them at moderate-to-high risk of stroke, with or without heart failure. We used Cox proportional hazards regression models adjusted for baseline characteristics and drugs to investigate the association of digoxin with all-cause mortality, vascular death, and sudden death. ROCKET AF was registered with ClinicalTrials.gov, number NCT00403767. In 14 171 randomly assigned patients, digoxin was used at baseline in 5239 (37%). Patients given digoxin were more likely to be female (42% vs 38%) and have a history of heart failure (73% vs 56%), diabetes (43% vs 38%), and persistent AF (88% vs 77%; p<0·0001 for each comparison). After adjustment, digoxin was associated with increased all-cause mortality (5·41 vs 4·30 events per 100 patients-years; hazard ratio 1·17; 95% CI 1·04–1·32; p=0·0093), vascular death (3·55 vs 2·69 per 100 patient-years; 1·19; 1·03–1·39, p=0·0201), and sudden death (1·68 vs 1·12 events per 100 patient-years; 1·36; 1·08–1·70, p=0·0076). Digoxin treatment was associated with a significant increase in all-cause mortality, vascular death, and sudden death in patients with AF. This association was independent of other measured prognostic factors, and although residual confounding could account for these results, these data show the possibility of digoxin having these effects. A randomised trial of digoxin in treatment of AF patients with and without heart failure is needed. Janssen Research & Development and Bayer HealthCare AG.

•Patients with rheumatic heart disease (RHD) have a high risk of mortality due to heart failure (HF).•There are no proven treatments for improving clinical outcomes in these patients.•The Digoxin in RHD is the first RCT to evaluate the impact of digoxin on mortality and HF in RHD. Rheumatic heart disease (RHD), is a public health problem in low and middle-income countries. It causes high morbidity and mortality due to heart failure (HF), but there are no randomized trials of HF-treatments in these patients. Digoxin is an inexpensive drug that is widely used in RHD despite a lack of data on its effect on clinical outcomes. The Digoxin in RHD (Dig-RHD) trial will evaluate the impact of the drug on clinical outcomes in patients with RHD. The Dig-RHD trial is an investigator-initiated multicenter, pragmatic, randomized placebo-controlled, parallel-arm, superiority trial. Symptomatic adult patients with RHD were randomized to receive oral digoxin or matching placebo on a background of usual care. The primary outcome is a composite of all-cause death, new-onset or worsening HF. Key secondary outcomes are, all-cause death, HF-related death, hospitalization for HF, sudden death, and self-reported quality of life. Patients were enrolled at 12 academic medical centers in India, beginning in February 2022. Enrolment of 1769 patients was completed in August 2024. One interim review of the data by the independent Data Safety Monitoring Board, after half the primary outcome events had accrued, indicated no safety signals. The last follow-up visits are scheduled to complete in December 2025. Dig-RHD is the first randomized trial of digoxin in RHD powered for clinical outcomes, and the results will have major implications for the routine management of patients with RHD. (Clinical trial registration: CTRI/2021/04/032858)

The Digitalis Investigation Group previously reported no difference in mortality between patients with heart failure who received digoxin and those who received placebo. In this post hoc analysis, men and women in the trial were analyzed separately. Digoxin therapy had no effect on mortality in men but was associated with an increase in overall mortality among women (33.1 percent in the digoxin group vs. 28.9 percent in the placebo group). Digoxin therapy was associated with an increase in overall mortality among women with heart failure. In 1997, the Digitalis Investigation Group reported the results of a randomized, double-blind, placebo-controlled trial evaluating the efficacy of digoxin therapy for patients with heart failure. 1 The investigators found that digoxin did not reduce overall mortality or three of the five secondary outcomes (death due to cardiovascular causes, death due to worsening heart failure, and the combined end point of death or hospitalization due to worsening heart failure in an ancillary trial). However, digoxin did decrease the risk of hospitalization for worsening heart failure and the overall risk of hospitalization during three years of follow-up. Since these results were published, . . .

Background Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the treatment of type 2 diabetes mellitus are known to delay gastric emptying (GE). The potential effect of the GLP-1 RA dulaglutide on the pharmacokinetics (PK) of four orally administered drugs and on the pharmacodynamic (PD) effect of warfarin was investigated. Methods In four separate clinical pharmacology studies, digoxin, warfarin, atorvastatin and Ortho-Cyclen ® were orally administered to healthy subjects with and without a subcutaneous dose of dulaglutide 1.5 mg. The effect of dulaglutide coadministration was assessed based on the PK parameters of key analytes. For warfarin PD, the effect of dulaglutide on the international normalized ratio (INR) was evaluated. Results Areas under the concentration–time curves (AUCs) with and without dulaglutide were similar for all analytes except atorvastatin, where it was reduced by 21%. Maximum concentrations ( C max ) were generally lower following coadministration with dulaglutide, with statistically significant reductions (90% confidence intervals of geometric least squares means ratios outside 0.80–1.25) for all analytes except R-warfarin. For all analytes, there was a general trend for the time to C max ( t max ) to increase following coadministration with dulaglutide. For warfarin, dulaglutide coadministration had no statistically significant effect on the maximum INR (INR max ); however, a 2% increase in area under the INR curve (AUC INR ) was observed. Conclusions Dulaglutide did not affect the absorption of the tested medications to a clinically relevant degree. Based on the PK and PD evaluations, no dose adjustments for digoxin, warfarin, atorvastatin and Ortho-Cyclen ® are recommended when coadministered with dulaglutide. Clinical trial registration numbers NCT01458210, NCT01436201, NCT01432938, and NCT01250834.