Rate control efficacy in permanent atrial fibrillation:a comparison between lenient versus strict rate control in patients with and without heart failure. Background, aims, and design of RACE II

BACKGROUND: Recent studies demonstrated that rate control is an acceptable alternative for rhythm control in patients with persistent atrial fibrillation (AF). However, optimal heart rate during AF is still unknown. OBJECTIVE: To show that in patients with permanent AF, lenient rate control is not inferior to strict rate control in terms of cardiovascular mortality, morbidity, neurohormonal activation, New York Heart Association class for heart failure, left ventricular function, left atrial size, quality of life, and costs. METHODS: The RACE II study is a prospective multicenter trial in The Netherlands that will randomize 500 patients with permanent AF (< or = 12 months) to strict or lenient rate control. Strict rate control is defined as a mean resting heart rate < 80 beats per minute (bpm) and heart rate during minor exercise < 110 bpm. After reaching the target, a 24-hour Holter monitoring will be performed. If necessary, drug dose reduction and/or pacemaker implantation will be performed. Lenient rate control is defined as a resting heart rate < 110 bpm. Patients will be seen after 1, 2, and 3 months (for titration of rate control drugs) and yearly thereafter. We anticipate a 25% 2.5-year cardiovascular morbidity and mortality in both groups. RESULTS: Enrollment started in January 2005 in 29 centers in The Netherlands and is expected to be concluded in June 2006. Follow-up will be at least 2 years with a maximum of 3 years. CONCLUSION: This study should provide data how to treat patients with permanent AF

Evaluation of Importance of Central Effects of Atenolol and Metoprolol Measured by Heart Rate Variability During Mental Performance Tasks, Physical Exercise, and Daily Life in Stable Postinfarct Patients

Background Physical exercise and mental work cause alterations in cardiac autonomic control. beta-Blockers protect the heart against stress, and this effect may be in part centrally mediated. In this context, the lipophilicity of the drug would be clinically relevant. Methods and Results Thirty postinfarct patients were randomized to receive 100 mg atenolol or 200 mg metoprolol CR in a double-blind, crossover manner, each for a 6-week period. Heart rate (HR) variability was used to study autonomic effects during mental and physical stress and to study circadian variations. Mean 24-hour HR decreased from 77+/-7 to 60+/-6 beats per minute after atenolol and to 62+/-6 beats per minute after metoprolol (P=.046). At baseline, mental performance tasks did not affect HR, but decreased HR variability (SDNN index from 51+/-26 to 30+/-13 milliseconds [ms], P Conclusions In stable postinfarct patients, chronic treatment with metoprolol and atenolol attenuates the reduction in HR variability induced by mental performance tasks, but the effects during exercise are limited. beta-Blockers do not appear to increase vagal tone in this stable patient group. The point of action in these patients is mainly a reduction in HR, probably due to a reduction in stress-induced sympathetic activation. Clinically significant differences between atenolol and metoprolol were absent, indicating that the degree of lipophilicity does not distinguish among the beta-blockers what their salutary effects are on HR variability during the specific challenges used

Open-Label, Multicenter Study of Flecainide Acetate Oral Inhalation Solution for Acute Conversion of Recent-Onset, Symptomatic Atrial Fibrillation to Sinus Rhythm

BACKGROUND: Oral and intravenous flecainide is recommended for cardioversion of atrial fibrillation. In this open-label, dose-escalation study, the feasibility of delivering flecainide via oral inhalation (flecainide acetate inhalation solution) for acute conversion was evaluated. We hypothesized that flecainide delivered by oral inhalation would quickly reach plasma concentrations sufficient to restore sinus rhythm in patients with recent-onset atrial fibrillation. METHODS: Patients (n=101) with symptomatic atrial fibrillation (for ≤48 hours) self administered flecainide acetate inhalation solution using a nebulizer (30 mg [n=10], 60 mg [n=22], 90 mg [n=21], 120 mg [n=19], and 120 mg in a formulation containing saccharin [n=29]). Electrocardiograms and flecainide plasma concentrations were obtained, cardiac rhythm using 4-hour Holter was monitored, and adverse events were recorded. RESULTS: Conversion rates increased with dose and with the maximum plasma concentrations of flecainide. At the highest dose, 48% of patients converted to sinus rhythm within 90 minutes from the start of inhalation. Among patients who achieved a maximum plasma concentration >200 ng/mL, the conversion rate within 90 minutes was 50%; for those who achieved a maximum plasma concentration <200 ng/mL, it was 24%. Conversion was rapid (median time to conversion of 8.1 minutes from the end of inhalation), and conversion led to symptom resolution in 86% of the responders. Adverse events were typically mild and transient and included: cough, throat pain, throat irritation; at the highest dose with the formulation containing saccharin, these adverse events were reported by 41%, 14%, and 3% of patients, respectively. Cardiac adverse events consistent with those observed with oral and intravenous flecainide were uncommon and included postconversion pauses (n=2), bradycardia (n=1), and atrial flutter with 1:1 atrioventricular conduction (n=1); none required treatment, and all resolved without sequelae. CONCLUSIONS: Administration of flecainide via oral inhalation was shown to be safe and to yield plasma concentrations of flecainide sufficient to restore sinus rhythm in patients with recent-onset atrial fibrillation. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03539302