digoxin and edoxaban

Efficacy and safety of dronedarone was shown in the ATHENA trial for paroxysmal or persistent atrial fibrillation (AF) patients. Further trials revealed safety concerns in patients with heart failure and permanent AF. This review summarizes insights from recent real-world studies and meta-analyses, including reports on efficacy, with focus on liver safety, mortality risk in patients with paroxysmal/persistent AF, and interactions of dronedarone with direct oral anticoagulants. Reports of rapidly progressing liver failure in dronedarone-prescribed patients in 2011 led to regulatory cautions about potential liver toxicity. Recent real-world evidence suggests dronedarone liver safety profile is similar to other antiarrhythmics and liver toxicity could be equally common with many Class III antiarrhythmics. Dronedarone safety concerns (increased mortality in patients with permanent AF) were raised based on randomized controlled trials (RCT) (ANDROMEDA and PALLAS), but comedication with digoxin may have increased the mortality rates in PALLAS, considering the dronedarone-digoxin pharmacokinetic (PK) interaction. Real-world data on apixaban-dronedarone interactions and edoxaban RCT observations suggest no significant safety risks for these drug combinations. Median trough plasma concentrations of dabigatran 110 mg during concomitant use with dronedarone are at acceptable levels, while PK data on the rivaroxaban-dronedarone interaction are unavailable. In RCTs and real-world studies, dronedarone significantly reduces AF burden and cardiovascular hospitalizations, and demonstrates a low risk for proarrhythmia in patients with paroxysmal or persistent AF. The concerns on liver safety must be balanced against the significant reduction in hospitalizations in patients with non-permanent AF and low risk for proarrhythmias following dronedarone treatment.

Topics: Anti-Arrhythmia Agents; Antithrombins; Atrial Fibrillation; Chemical and Drug Induced Liver Injury; Dabigatran; Digoxin; Dronedarone; Drug Interactions; Factor Xa Inhibitors; Heart Failure; Hospitalization; Humans; Mortality; Pyridines; Randomized Controlled Trials as Topic; Thiazoles

The oral anticoagulant edoxaban, a factor Xa inhibitor, will likely be coadministered with digoxin in some patients with atrial fibrillation. Both drugs are substrates for P-glycoprotein. The objective of this phase 1, parallel study was to assess the effects of coadministration of both drugs on their respective pharmacokinetics (PK) and pharmacodynamics (PD). Forty-eight subjects, aged 18 to 45 years, received either edoxaban 60 mg once daily × 7 days (n = 24) or digoxin 0.25 mg twice daily × 2 days and once daily × 5 days (n = 24) and then concomitantly for 7 days. Serial blood and urine samples were collected for digoxin and edoxaban concentrations on days 7 and 14. Serial coagulation assays were measured for edoxaban on days 7 and 14. Edoxaban PK parameters demonstrated mild increases in area under the curve and peak concentrations of 9.5% and 15.6%, respectively, when coadministered with digoxin. Although digoxin PK parameters demonstrated increased area under the curve and peak concentrations of 8.3% and 28%, respectively, plasma concentrations were within the established therapeutic range. Edoxaban PD were consistent with PK. Both drugs were well tolerated alone or in combination. No clinically significant changes in PK, PD, or renal elimination were observed with concomitant administration of edoxaban and digoxin.

Topics: Adolescent; Adult; Anticoagulants; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cardiotonic Agents; Cross-Over Studies; Digoxin; Drug Interactions; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Pyridines; Thiazoles; Time Factors; Young Adult