Expert Consensus on Comprehensive Early Rhythm Control in Addition to Guideline-Based Care for Atrial Fibrillation: A Modified Delphi Survey.

Atrial fibrillation (AF) practice guidelines recommend a rhythm-control strategy to improve symptoms and quality of life, noting the side effects of antiarrhythmic drugs and catheter ablation. Emerging evidence indicates that comprehensive early rhythm control with antiarrhythmic drugs or catheter ablation is associated with a lower risk of adverse cardiovascular outcomes versus the usual care. Using an online modified Delphi survey approach, perspectives and expert consensus among electrophysiologists were examined through a series of ranking and likelihood questions around treatment decision-making on (1) the use of comprehensive early rhythm-control strategies in patients with AF based on guidelines and emerging research and (2) treatment selection factors. A panel of 17 electrophysiologists reached a consensus on using early rhythm control (median 90, interquartile range 14) based on the view that early intervention improved cardiovascular outcomes (mean rank 1.6 of 3, 82% within 1 SD) and symptoms (1.8 of 3, 41%). AF-related symptoms were identified as the most important in making a treatment initiation decision (1.1 of 7, 88%), followed by AF type (2.5 of 7, 82%). Participants were most likely to initiate treatment at AF symptom onset (median 80; interquartile range 6). In making treatment selection decisions, participants ranked short-term/long-term safety (1.9 of 7, 88%) and efficacy (1.8 of 7, 53%) as the top 2 considerations. In conclusion, experts were in favor of early rhythm control; however, additional research is needed to address the role that early rhythm-control strategies play in current AF treatment management algorithms.

Effect of dronedarone vs. placebo on atrial fibrillation progression: a post hoc analysis from ATHENA trial.

AIMS: This post hoc analysis of the ATHENA trial (NCT00174785) assessed the effect of dronedarone on the estimated burden of atrial fibrillation (AF)/atrial flutter (AFL) progression to presumed permanent AF/AFL, and regression to sinus rhythm (SR), compared with placebo. METHODS AND RESULTS: The burden of AF/AFL was estimated by a modified Rosendaal method using available electrocardiograms (ECG). Cumulative incidence of permanent AF/AFL (defined as ≥6 months of AF/AFL until end of study) or permanent SR (defined as ≥6 months of SR until end of study) were calculated using Kaplan-Meier estimates. A log-rank test was used to assess statistical significance. Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were estimated using a Cox model, adjusted for treatment group. Of the 4439 patients included in this analysis, 2208 received dronedarone, and 2231 placebo. Baseline and clinical characteristics were well balanced between groups. Overall, 304 (13.8%) dronedarone-treated patients progressed to permanent AF/AFL compared with 455 (20.4%) treated with placebo (P < 0.0001). Compared with those receiving placebo, patients receiving dronedarone had a lower cumulative incidence of permanent AF/AFL (log-rank P < 0.001; HR: 0.65; 95% CI: 0.56-0.75), a higher cumulative incidence of permanent SR (log-rank P < 0.001; HR: 1.19; 95% CI: 1.09-1.29), and a lower estimated AF/AFL burden over time (P < 0.01 from Day 14 to Month 21). CONCLUSION: These results suggest that dronedarone could be a useful antiarrhythmic drug for early rhythm control due to less AF/AFL progression and more regression to SR vs. placebo, potentially reflecting reverse remodeling. CLINICAL TRIAL REGISTRATION: NCT00174785.

Healthcare resource utilization in patients with newly diagnosed atrial fibrillation in the United States.

OBJECTIVES: To summarize healthcare resource utilization (HCRU) in patients with newly diagnosed (incident) paroxysmal or persistent atrial fibrillation (AF). METHODS: This retrospective, observational cohort study assessed HCRU among patients with incident paroxysmal or persistent AF using data from 1 January 2015 to 30 September 2019 in the IBM MarketScan® Research Databases. RESULTS: A total of 50,796 patients were identified in the overall incident AF cohort. Rates of all-cause inpatient hospital stays, all-cause emergency room visits, and all-cause outpatient visits in the overall incident cohort were 46.8, 114.7, and 2,752.7 events per 100 patient-years (PY), respectively. Rates of cardiovascular-related inpatient stays for the overall population were 11.3 events per 100 PY. During follow-up, 50.4% of the overall cohort filled prescriptions for direct-acting oral anticoagulants and 5.0% had catheter ablation. CONCLUSIONS: Advances in anticoagulation and ablation have been realized since previously published HCRU analyses of patients with atrial fibrillation. This update suggests that HCRU among patients with incident AF in the US remains high with some subgroups of patients receiving more specialized care.

Predictors of dronedarone plasma drug concentrations and effect on atrial fibrillation/atrial flutter recurrence: Analyses from the EURIDIS and ADONIS studies.

BACKGROUND: In this post hoc analysis, we assessed patient characteristics as predictors of dronedarone trough concentrations and characterized the relationship of trough concentrations of dronedarone with its efficacy and safety. HYPOTHESIS: Dronedarone is recommended as a 400 mg twice daily dose taken orally with meals. We hypothesize that drug concentration/bioavailability of dronedarone, measured as above- and below-median trough concentrations, does not impact the efficacy outcomes. METHODS: Average trough concentrations (Ctrough_avg ) across multiple timepoints were calculated for each patient, and patient Ctrough_avg values were categorized as below-median or above-median concentrations. The effect of patient baseline characteristics on dronedarone Ctrough_avg was assessed in the below-median versus above-median groups. The effect of dronedarone in each Ctrough_avg group versus placebo on risk of first atrial fibrillation/atrial flutter (AF/AFL) recurrence and safety was also evaluated. RESULTS: Overall, 1795 plasma samples were available from 507 dronedarone-treated patients. An above-median Ctrough_avg was associated with age ≥75 years, female sex, lower weight, higher pacemaker use, and higher oral anticoagulant use. The risk of adjudicated first AF/AFL recurrence was significantly lower with dronedarone versus placebo in the below-median (hazard ratio [HR]: 0.71; 95% confidence interval [CI]: 0.56-0.91; p = .0054) and above-median groups (HR: 0.63; 95% CI: 0.50-0.81; p = .0002). No difference in risk of AF/AFL recurrence was observed between the above- and below-median groups. Safety and tolerability of dronedarone were similar between groups. CONCLUSION: Significant reduction in AF/AFL recurrence was observed in patients treated with dronedarone versus placebo, regardless of dronedarone concentrations above or below the median value.

Endotoxic shock alters the pharmacokinetics of lidocaine and monoethylglycinexylidide.

Significant hepatic dysfunction occurs following endotoxin administration. Although the metabolism of lidocaine to one of the primary metabolites of lidocaine, monoethylglycinexylidide (MEGX), has been used as a marker of hepatic function under various conditions, it remains unknown whether these compounds can be used in vivo to evaluate hepatic function in a rat model of endotoxic shock. To study this, cytochrome P450-3A4 (CYP3A4) was determined after harvesting hepatic microsomes, hepatic blood flow was determined using radioactive microspheres, and the pharmacokinetics of lidocaine and MEGX were evaluated. Adult male Sprague-Dawley rats were divided into endotoxin (45 mg/kg, intraperitoneally; n = 28) or control (n = 32) groups. The CYP3A4 was significantly reduced after endotoxic shock. Carboxylesterase (hydrolase S) content, which was used as a control for microsomal protein, was not significantly different between groups. Total hepatic blood flow was significantly decreased (36.2 +/- 8.4 mL/min/100 g tissue vs. 120.4 +/- 10.6 mL/min/100 g tissue), which was due to the decreased portal blood flow. For the lidocaine and MEGX experiment, lidocaine (2 mg/kg) was administered followed by serial blood samples collected up to 2 h for determination of serum lidocaine and MEGX concentrations. Mean arterial pressure (MAP) was recorded throughout the experiment. The MAP was significantly lower in the endotoxin treated rats vs. control 7.5 to 8 h following endotoxin administration. Serum concentrations of lidocaine were higher in endotoxic shock versus control animals at 2 h following lidocaine administration (1.5 +/- 0.13 mg/L vs. 0.11 +/- 0.03 mg/L). Similarly, MEGX concentrations were significantly higher in endotoxic shock versus control animals (0.55 +/- 0.04 mg/L vs. 0.16 +/- 0.02, respectively) under such conditions. These data demonstrate that the elimination of lidocaine and MEGX is impaired during endotoxic shock. The elevated lidocaine and MEGX concentrations are likely to be the result of primarily reduced hepatic blood flow and secondarily due to impaired CYP450, one of which was CYP3A4. The reduced elimination of MEGX concentrations is not due to decreased hepatic metabolism of the compound via carboxylesterase. The ratio of MEGX to lidocaine concentrations, which decreased significantly following endotoxic shock, appears to be a useful measure of hepatic function during endotoxic shock where profound reductions of hepatic blood flow are observed in addition to significant reductions in CYP450. The use of only MEGX concentrations in this endotoxic shock model is not useful in evaluating liver function.