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Orally Inhaled Flecainide for Conversion of AF to Sinus Rhythm
Quick Takes
- As the prevalence of AF increases, there is a need for pharmacologic treatments to convert AF to sinus rhythm (SR) as a single dose, with a high efficacy rate and with the ability to be safely administered in an outpatient clinic setting.
- In this prospective multicenter study, a single dose of 120 mg inhaled flecainide acetate (FlecIH) resulted in a high rate of conversion to SR at 90 minutes without serious side effects.
Study Questions:
What is the efficacy and safety of a single dose of 120 mg of flecainide acetate oral inhalation solution (FlecIH) administered in a monitored outpatient setting for the conversion of recent-onset atrial fibrillation (AF) to sinus rhythm (SR)?
Methods:
INSTANT (INhalation of flecainide to convert recent-onset SympTomatic Atrial fibrillatioN to sinus rhyThm) was a multicenter, international, prospective study. Patients were included if they were between 18 and 85 years of age with newly diagnosed or recurrent AF (≤48 hours). Patients with hemodynamic instability or a contraindication to flecainide were excluded. A single 120 mg dose of FlecIH was administered by nebulizer over 8 minutes. The SR conversion rate at 90 minutes was the primary endpoint. Patients were followed for recurrence until discharged. Pharmacokinetics and pharmacodynamics of flecainide were also reported.
Results:
In a modified intention-to-treat population of 81 patients, which excluded patients who converted to SR before drug administration as well as recent ingestion of flecainide (as found in baseline blood levels), the cumulative conversion rate at 90 minutes post-dose was 46.9% at a median time of about 14.6 minutes. One or more adverse effects were reported in 67% of the safety population (n = 98) and 97.3% were classified as mild-to-moderate severity. Most adverse effects were reported within 40 minutes and were cough or oropharyngeal discomfort or pain. None led to discontinuation of the drug administration.
The median time to discharge in patients who converted to SR was 2.5 hours. Slow atrial flutter (AFl) was reported in seven patients (8.2%), two of which converted from AF to AFl before converting to SR. The other five patients were electrically cardioverted to restore SR. Five patients (5.1%) experienced six cardiovascular adverse effects including hypotension, bradycardia, both, or transient 1:1 AFl. Three were asymptomatic and only two of the six were considered severe. One patient required a normal saline intravenous (IV) bolus for hypotension. Peak plasma concentrations of flecainide occurred at 1-minute post-dose with similar levels in patients who did versus did not convert to SR.
Conclusions:
In this phase 2 multicenter study, administration of 120 mg FlecIH resulted in a 90-minute cardioversion rate of slightly less than 50% of patients. Adverse effects were frequent and mostly related to the route of administration.
Perspective:
Oral flecainide is a commonly administered antiarrhythmic drug in the United States for a select patient population with AF and structurally normal hearts. IV flecainide is available in Europe. The rate of cardioversion to SR with single-dose flecainide observed in this study was lower than the 57-80% observed in other oral and IV placebo-controlled trials. However, in those studies, the observation period to measure pharmacologic cardioversion was longer. These early results with FlecIH warrant additional study. Given the formulation, it may be difficult to design a true placebo-controlled trial. Therefore, an approach with an active comparator such as IV flecainide could be used, as the onset of oral flecainide is slower.
Clinical Topics: Arrhythmias and Clinical EP, Atrial Fibrillation/Supraventricular Arrhythmias, Cardiovascular Care Team
Keywords: Atrial Fibrillation, Flecainide
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