Orally Inhaled Flecainide for Conversion of Atrial Fibrillation to Sinus Rhythm: INSTANT Phase 2 Trial.

BACKGROUND: INSTANT (INhalation of flecainide to convert recent-onset SympTomatic Atrial fibrillatioN to sinus rhyThm) was a multicenter, open-label, single-arm study of flecainide acetate oral inhalation solution (FlecIH) for acute conversion of recent-onset (≤48 hours) symptomatic atrial fibrillation (AF) to sinus rhythm. OBJECTIVES: This study investigated the efficacy and safety in 98 patients receiving a single dose of FlecIH delivered via oral inhalation. METHODS: Patients self-administered FlecIH over 8 minutes in a supervised medical setting using a breath-actuated nebulizer and were continuously monitored for 90 minutes using a 12-lead Holter. RESULTS: Mean age was 60.5 years, mean body mass index was 27.0 kg/m2, and 34.7% of the patients were women. All patients had ≥1 AF-related symptoms at baseline, and 87.8% had AF symptoms for ≤24 hours. The conversion rate was 42.6% (95% CI: 33.0%-52.6%) with a median time to conversion of 14.6 minutes. The conversion rate was 46.9% (95% CI: 36.4%-57.7%) in a subpopulation that excluded predose flecainide exposure for the current AF episode. Median time to discharge among patients who converted was 2.5 hours, and only 2 patients had experienced AF recurrence by day 5. In the conversion-no group, 44 (81.5%) patients underwent electrical cardioversion by day 5. The most common adverse events were related to oral inhalation of flecainide (eg, cough, oropharyngeal irritation/pain), which were mostly of mild intensity and limited duration. CONCLUSIONS: The risk-benefit of orally inhaled FlecIH for acute cardioversion of recent-onset AF appears favorable. FlecIH could provide a safe, effective, and convenient first-line therapeutic option. (INhalation of Flecainide to Convert Recent Onset SympTomatic Atrial Fibrillation to siNus rhyThm [INSTANT]; NCT03539302).

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.

The effect of rate control on quality of life in patients with permanent atrial fibrillation: data from the RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation II) study.

OBJECTIVES: The aim of this study was to investigate the influence of rate control on quality of life (QOL). BACKGROUND: The RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation II) trial showed that lenient rate control is not inferior to strict rate control in terms of cardiovascular morbidity and mortality. The influence of stringency of rate control on QOL is unknown. METHODS: In RACE II, a total of 614 patients with permanent atrial fibrillation (AF) were randomized to lenient (resting heart rate [HR] <110 beats/min) or strict (resting HR <80 beats/min, HR during moderate exercise <110 beats/min) rate control. QOL was assessed in 437 patients using the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) questionnaire, AF severity scale, and Multidimensional Fatigue Inventory-20 (MFI-20) at baseline, 1 year, and end of study. QOL changes were related to patient characteristics. RESULTS: Median follow-up was 3 years. Mean age was 68 ± 8 years, and 66% were males. At the end of follow-up, all SF-36 subscales were comparable between both groups. The AF severity scale was similar at baseline and end of study. At baseline and at end of study there were no differences in the MFI-20 subscales between the 2 groups. Symptoms at baseline, younger age, and less severe underlying disease, rather than assigned therapy or heart rate, were associated with QOL improvements. Female sex and cardiovascular endpoints during the study were associated with worsening of QOL. CONCLUSIONS: Stringency of heart rate control does not influence QOL. Instead, symptoms, sex, age, and severity of the underlying disease influence QOL. (Rate Control Efficacy in Permanent Atrial Fibrillation; NCT00392613).

Effect of lenient versus strict rate control on cardiac remodeling in patients with atrial fibrillation data of the RACE II (RAte Control Efficacy in permanent atrial fibrillation II) study.

OBJECTIVES: The aim of this study was to evaluate echocardiographic remodeling in permanent atrial fibrillation (AF) patients treated with either lenient or strict rate control. BACKGROUND: It is unknown whether in permanent AF, lenient rate control is associated with more adverse cardiac remodeling than strict rate control. METHODS: Echocardiography was conducted at baseline and at follow-up in 517 patients included in the RACE II (RAte Control Efficacy in permanent atrial fibrillation II) trial. Echocardiographic parameters were compared between patients randomized to lenient rate control (n = 261) or strict rate control (n = 256). RESULTS: Baseline echocardiographic parameters were comparable between patients randomized to lenient and strict rate control. Between baseline and follow-up, significant adverse atrial or ventricular remodeling was not observed in either group. There were also no significant differences in atrial and ventricular remodeling between patients who continuously had heart rates between 80 and 110 beats/min and patients who continuously had heart rates <80 beats/min during follow-up. Lenient rate control was not independently associated with changes in echocardiographic parameters: mean adjusted effect on left atrial size was 1.6 mm (p = 0.09) and 1.1 mm on left ventricular end-diastolic diameter (p = 0.23). Instead, female sex was independently associated with adverse remodeling: mean adjusted effect on left atrial size was 2.4 mm (p = 0.02) and 6.5 mm on left ventricular end-diastolic diameter (p < 0.0001). CONCLUSIONS: Female sex, not lenient rate control, seemed to be associated with significant adverse cardiac remodeling in patients with permanent AF such as those enrolled in the RACE II study. (RAte Control Efficacy in Permanent Atrial Fibrillation [RACE II]; NCT00392613).

Lenient versus strict rate control in patients with atrial fibrillation.

BACKGROUND: Rate control is often the therapy of choice for atrial fibrillation. Guidelines recommend strict rate control, but this is not based on clinical evidence. We hypothesized that lenient rate control is not inferior to strict rate control for preventing cardiovascular morbidity and mortality in patients with permanent atrial fibrillation. METHODS: We randomly assigned 614 patients with permanent atrial fibrillation to undergo a lenient rate-control strategy (resting heart rate <110 beats per minute) or a strict rate-control strategy (resting heart rate <80 beats per minute and heart rate during moderate exercise <110 beats per minute). The primary outcome was a composite of death from cardiovascular causes, hospitalization for heart failure, and stroke, systemic embolism, bleeding, and life-threatening arrhythmic events. The duration of follow-up was at least 2 years, with a maximum of 3 years. RESULTS: The estimated cumulative incidence of the primary outcome at 3 years was 12.9% in the lenient-control group and 14.9% in the strict-control group, with an absolute difference with respect to the lenient-control group of -2.0 percentage points (90% confidence interval, -7.6 to 3.5; P<0.001 for the prespecified noninferiority margin). The frequencies of the components of the primary outcome were similar in the two groups. More patients in the lenient-control group met the heart-rate target or targets (304 [97.7%], vs. 203 [67.0%] in the strict-control group; P<0.001) with fewer total visits (75 [median, 0], vs. 684 [median, 2]; P<0.001). The frequencies of symptoms and adverse events were similar in the two groups. CONCLUSIONS: In patients with permanent atrial fibrillation, lenient rate control is as effective as strict rate control and is easier to achieve. (ClinicalTrials.gov number, NCT00392613.)

Morphology-enhanced atrial event classification improves sensing in pacemakers.

BACKGROUND: In atrial-based pacing, appropriate therapy and reliable diagnostics depend on detection and discrimination of atrial signals. Accurate classification of atrial events is mainly confounded by oversensing of ventricular far-field R-wave signals (FFRW), but attempts to reject FFRWs by manipulating atrial sensitivity and/or postventricular atrial blanking period (PVAB) may result in undersensing (especially of atrial fibrillation, AF) or in 2:1 atrial flutter detection. The objective of this study is therefore to evaluate if such methods can be improved by morphology-enhanced atrial event classification (MORPH). METHODS: Twenty-four-hour ambulatory atrial electrograms were recorded from continuous telemetry of digital pacemakers. Half of the recording was used for collecting two individual morphology parameters that discriminated P-waves from FFRWs in every patient (learning phase). The other half was used to test the MORPH algorithm against traditional methods (classification phase). RESULTS: In 44/48 patients, data were suitable for analysis. Average P and FFRW amplitudes were 1.96 mV versus 0.61 mV (P < 0.001). The interval between ventricular events and FFRW oversensing (VA interval) averaged at 14 ms during sensing and at 118 ms during pacing in the ventricle. Compared to nominal ("Factory") settings, the MORPH algorithm improved the sensitivity for P-wave recognition from 97.2% to 99.2%, the specificity from 91.9% to 99.96%, and the accuracy from 95.3% to 99.4% (P < 0.01 for all). CONCLUSIONS: By improving atrial signal discrimination, morphology analysis of atrial electrograms allows for high atrial sensitivity settings, and potentially improves the reliability of atrial arrhythmia diagnostics in heart rhythm devices.

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.