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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.

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.

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 The novel iron-based phosphate binder sucroferric oxyhydroxide is being investigated for the treatment of hyperphosphatemia. Patients with chronic kidney disease often have multiple comorbidities that may necessitate the daily use of several types of medication. Therefore, the potential pharmacokinetic drug–drug interactions between sucroferric oxyhydroxide and selected drugs commonly taken by dialysis patients were investigated. Methods Five Phase I, single-center, open-label, randomized, three-period crossover studies in healthy volunteers investigated the effect of a single dose of sucroferric oxyhydroxide 1 g (based on iron content) on the pharmacokinetics of losartan 100 mg, furosemide 40 mg, omeprazole 40 mg, digoxin 0.5 mg and warfarin 10 mg. Pharmacokinetic parameters [including area under the plasma concentration–time curve (AUC) from time 0 extrapolated to infinite time (AUC 0–∞ ) and from 0 to 24 h (AUC 0–24 )] for these drugs were determined: alone in the presence of food; with sucroferric oxyhydroxide in the presence of food; 2 h after food and sucroferric oxyhydroxide administration. Results Systemic exposure based on AUC 0–∞ for all drugs, and AUC 0–24 for all drugs except omeprazole (for which AUC 0–8 h was measured), was unaffected to a clinically significant extent by the presence of sucroferric oxyhydroxide, irrespective of whether sucroferric oxyhydroxide was administered with the drug or 2 h earlier. Conclusions There is a low risk of drug–drug interactions between sucroferric oxyhydroxide and losartan, furosemide, digoxin and warfarin. There is also a low risk of drug–drug interaction with omeprazole (based on AUC 0–∞ values). Therefore, sucroferric oxyhydroxide may be administered concomitantly without the need to adjust the dosage regimens of these drugs.

Although digoxin is one of the most commonly prescribed drugs for the treatment of heart failure, there is uncertainty about its long-term efficacy and safety. 1 – 3 Several recent short-term, randomized trials indicated that withdrawing digoxin worsens functional status, exercise capacity, and the left ventricular ejection fraction in patients with heart failure. 4 , 5 However, the long-term effect of digoxin on mortality and hospitalization for heart failure or other causes is unknown. We conducted a randomized, double-blind, placebo-controlled trial to evaluate the effects of digoxin (Lanoxin, Glaxo Wellcome) on mortality from any cause (the primary end point) and on hospitalization for heart . . .

Direct oral anticoagulants (DOACs) are commonly co-prescribed with digoxin, but whether there is a drug interaction between them is unclear. We aimed to investigate potential drug interactions between DOACs and digoxin. We identified DOAC users during January 1, 2011–December 31, 2019 using data from Clinical Practice Research Datalink Aurum in cohort design with propensity score to compare the hazards of effectiveness cardiovascular and mortality outcomes and safety bleeding outcomes, respectively, in DOAC + digoxin users versus DOAC + beta-blocker users. A case-crossover design was conducted to compare odds of exposure to different drug initiation patterns in hazard period versus referent period. Of 397,459 DOAC users, we identified 25,251 co-prescribed digoxin and 109,779 co-prescribed beta-blockers in cohort study. A lower proportion of DOAC + digoxin users were men (46%) in contrast with that of DOAC + beta-blocker users (53%). Mean age of DOAC + digoxin users (77.1 years) were higher than DOAC + beta-blocker users (74.5 years). No increased risk of pharmacologically predictable DOAC safety outcomes or specific effectiveness outcomes was seen with DOAC + digoxin. A higher risk of all-cause mortality (hazard ratio: 1.35; 99% confidence interval [CI]: 1.14–1.61) was observed with DOAC + digoxin versus DOAC + beta-blockers. In the case-crossover study, a 24% higher odds of all-cause mortality was seen with initiating digoxin while taking DOAC (odds ratio: 1.24; 99% CI: 1.06–1.45); and a 63% higher odds was also seen with initiating DOAC while taking digoxin (odds ratio: 1.63; 99% CI: 1.41–1.88). We found no increased risk of bleeding when DOACs are used with digoxin, suggesting combined use does not lead to drug-drug interaction. Future work is recommended to investigate the underlying mechanism of association with all-cause mortality. This study aimed to examine potential drug interactions between direct oral anticoagulants (DOACs) (a drug class to prevent blood clots) and digoxin (treatment of abnormal heart rhythms). We compared a range of clinical outcomes in people prescribed DOAC and digoxin with people prescribed DOAC and beta-blockers (a treatment alternative to digoxin). We also used a new study design (case-crossover design) to compare the risk of clinical outcomes between different periods within a person as a validation. In both study designs, we found no increased risk of bleeding when DOACs are used with digoxin, suggesting combined use does not lead to drug-drug interaction. However, we found an increased risk of all-cause death associated with digoxin in DOAC users which requires further investigation. •Using direct oral anticoagulants (DOAC) with digoxin is safe regarding bleeding risk.•Risk of mortality associated with digoxin in DOAC users is increased.•New case-crossover design can study drug initiation patterns and reduce confounding.

PurposeTo perform a systematic umbrella review with meta-analysis to evaluate the certainty of evidence on mortality risk associated with digoxin use in patients with atrial fibrillation (AF) with or without heart failure (HF).MethodsWe systematically searched MEDLINE, Embase, and Web of Science databases from inception to 19 October 2021. We included systematic reviews and meta-analyses of observational studies investigating digoxin effects on mortality of adult patients with AF and/or HF. The primary outcome was all-cause mortality; secondary outcome was cardiovascular mortality. Certainty of evidence was evaluated by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool and the quality of systematic reviews/meta-analyses by the A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR2) tool.ResultsEleven studies accounting for 12 meta-analyses were included with a total of 4,586,515 patients. AMSTAR2 analysis showed a high quality in 1, moderate in 5, low in 2, and critically low in 3 studies. Digoxin was associated with an increased all-cause mortality (hazard ratio [HR] 1.19, 95% confidence interval [95%CI] 1.14–1.25) with moderate certainty of evidence and with an increased cardiovascular mortality (HR 1.19, 95%CI 1.06–1.33) with moderate certainty of evidence. Subgroup analysis showed that digoxin was associated with all-cause mortality both in patients with AF alone (HR 1.23, 95%CI 1.19–1.28) and in those with AF and HF (HR 1.14, 95%CI 1.12–1.16).ConclusionData from this umbrella review suggests that digoxin use is associated with a moderate increased risk of all-cause and cardiovascular mortality in AF patients regardless of the presence of HF.Trial registrationThis review was registered in PROSPERO (CRD42022325321).

The role of long-term vasodilator therapy in the care of asymptomatic patients with severe aortic regurgitation is of considerable interest. Aortic regurgitation results in an increase in left ventricular volume and thus in afterload; the left ventricle adapts by increasing left ventricular mass 1 . In patients with aortic regurgitation, vasodilators produce arteriolar vasodilatation, thereby increasing forward flow and reducing the amount of regurgitation, 2 which results in a short-term improvement in hemodynamics and left ventricular function 3 , 4 . In one symptomatic patient, hydralazine therapy for 14 months produced beneficial effects in terms of left ventricular function and symptoms, 5 but this finding . . .

Background This study aimed to compare the impact of digoxin versus beta-blocker on adverse clinical outcomes in patients with coexisting atrial fibrillation (AF) and heart failure (HF). Methods This study employed a target trial emulation with a clone-censor-weight approach to analyze data from 28,377 patients diagnosed with both AF and HF in the Clinical Data Analysis and Reporting System (CDARS) in Hong Kong between January 1, 2005, and December 31, 2017. Patients were followed up for up to 3 years or until the occurrence of clinical outcomes. The exposures were digoxin ( N  = 5351) versus beta-blocker ( N  = 7655) within a 90-day grace period. Absolute risks (ARs), risk differences, and risk ratios (RRs) with 95% confidence intervals (CIs) were estimated using weighted pooled logistic regression adjusted for demographic characteristics, comorbidities, and medication use. The primary outcome was all-cause mortality, while secondary outcomes included cardiovascular (CV) mortality, heart failure hospitalization, acute ischemic stroke, acute myocardial infarction, and pacemaker implantation. Results Over 3 years, digoxin was associated with a significantly higher risk of all-cause mortality ( AR : 51.2% vs. 42.2%; RR : 1.21; 95% CI : 1.17 to 1.26), CV mortality ( AR : 25.1% vs. 21.0%; RR : 1.20; 95% CI : 1.11 to 1.29), and heart failure hospitalization ( AR : 29.0% vs. 26.4%; RR : 1.10; 95% CI : 1.04 to 1.16). No significant differences were observed for acute ischemic stroke ( AR : 4.3% vs. 4.3%; RR : 1.00; 95% CI : 0.85 to 1.18), acute myocardial infarction ( AR : 4.6% vs. 4.3%; RR : 1.04; 95% CI : 0.88 to 1.23), or pacemaker implantation ( AR : 1.0% vs. 1.3%; RR : 0.74; 95% CI : 0.54 to 1.01). Conclusions In patients with coexisting AF and HF, digoxin was associated with significantly higher risks of all-cause mortality, cardiovascular mortality, and heart failure hospitalization compared to beta-blocker.