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Patients presenting within 36 hours after the onset of atrial fibrillation were randomly assigned to undergo early cardioversion or to receive rate-control medication followed by delayed cardioversion within 48 hours if there was no conversion to sinus rhythm. The wait-and-see approach was noninferior to early cardioversion for the primary outcome of sinus rhythm at 4 weeks.

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 . . .

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.

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.

•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)

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. 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. 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. Regression-based or IOSW approaches can be used to transport trial effect estimates to patients administrative/registry data, with only moderate reductions in precision.

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 Immunostimulatory and antiproliferative therapies have been widely used for the treatment of multiple warts. Recently, anti‐HPV activity of ionic contra viral therapy (ICVT) which is comprised of combined digoxin and furosemide has been demonstrated. Aim To evaluate and compare the effectiveness and safety of intralesional injection of Candida antigen, vitamin D3, and combined digoxin and furosemide in the treatment of multiple warts. Patients and Methods Seventy‐five patients with numerous warts were randomly assigned to one of three equal groups: Candida antigen, vitamin D3, or a combination of digoxin and furosemide. In the Candida antigen group, injections into the biggest wart were done. In the vitamin D3 and combined digoxin/furosemide groups, the agent was injected into each wart with a maximum of five injected warts. Injections were repeated every 2 weeks until clearance or for a total of five sessions. Results There was a statistically significant difference in the overall therapeutic response among the studied groups in favor of the intralesional Candida antigen group (60%), followed by the vitamin D3 group (48%) and the ionic contraviral therapy group (28%) (p = 0.02). However, the difference between both Candida antigen and vitamin D groups was not significant (p = 0.59). Conclusions Intralesional Candida antigen immunotherapy and vitamin D3 antiproliferative therapy are significantly more effective than ICVT. Limitations Short follow‐up period and relatively small sample size.

Background: Atrial fibrillation (AF) and heart failure (HF) often coexist. The aim was to investigate whether restoring sinus rhythm (SR) could improve cardiac function, symptoms, exercise capacity and quality of life (QoL) in patients with chronic heart failure. Methods: Patients with HF and persistent AF receiving guideline-recommended treatments, including anticoagulants, were eligible for the study. Patients were randomised to either rhythm (treated with amiodarone for at least 3 months prior to attempting biphasic external cardioversion and continued amiodarone long-term if SR was restored) or rate control. Anticoagulants were continued throughout the study regardless of rhythm, unless contraindications developed. Both groups were treated with beta blockers and/or digoxin to reduce the heart rate to <80 bpm at rest and <110 bpm after walking. Symptoms, walk distance (6-minute corridor walk test, 6MWT), QoL and cardiac function were assessed at baseline and 1 year. Results: 61 patients with HF and persistent AF (median duration 14 months (IQR 5 to 32)) were randomly assigned to a rate or rhythm control strategy. Of patients assigned to rhythm control (n = 30), 66% were in SR at 1 year, and 90% of those assigned to rate control (n = 31) achieved the heart rate target. At 1 year, NYHA class (p = 0.424) and 6MWT distance (p = 0.342) were similar between groups but patients assigned to rhythm control had improved LV function (p = 0.014), NT-proBNP concentration (p = 0.046) and QoL (p = 0.019) compared with those assigned to rate control. Greatest improvement was seen in patients in whom SR was maintained. Conclusion: Restoring SR in patients with AF and heart failure may improve QoL and LV function when compared with a strategy of rate control.

Objective We examined cognitive function in older hospitalised patients with chronic atrial fibrillation (AF). Design A prospective substudy of a multicentre randomised trial of an AF-specific disease management intervention (the Standard versus Atrial Fibrillation spEcific managmenT studY; SAFETY). Setting Three tertiary referral hospitals within Australia. Patients A total of 260 patients with chronic AF: mean age 72±11 years, 53% men, mean CHA2DS2-VASc score 4±2. Interventions Cognitive function was assessed at baseline (during inpatient stay) using the Montreal Cognitive Assessment (MoCA). Main Outcome Measures The extent of mild cognitive impairment (MCI—defined as a MoCA score <26) in AF patients and identification of independent predictors of MCI. Results Overall, 169 patients (65%, 95% CI 59% to 71%) were found to have MCI at baseline (mean MoCA score 21±3). Multiple deficits in cognitive domains were identified, most notably in executive functioning, visuospatial abilities and short-term memory. Predictors of MCI (age and sex-adjusted) were lower education level (technical/trade school level OR 6.00, 95% CI 2.07 to 17.42; <8 years school education OR 5.29, 95% CI 1.95 to 14.36 vs 8–13 years), higher CHA2DS2-VASc score (OR 1.46, 95% CI 1.23 to 1.74) and prescribed digoxin (OR 2.19, 95% CI 1.17 to 4.10). Conclusions MCI is highly prevalent amongst typically older high-risk patients hospitalised with AF. Routine assessment of cognitive function with adjustment of clinical management is indicated for this patient group.