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Inhaled flecainide promising for atrial fibrillation

Circulation: Arrhythmia and Electrophysiology
Reuters Health - 24/03/2022 - Inhaled flecainide shows promise for returning patients with recent-onset atrial fibrillation (AF) to sinus rhythm, a new study suggests.

This route of administration could shorten the duration of emergency room visits and reduce the volume of hospital admissions, they write in Circulation: Arrhythmia and Electrophysiology.

"Oral and intravenous treatments require more dedicated time and specific resources from the hospital including intravenous drug infusion materials," lead author Dr. Harry J.G.M. Crijns told Reuters Health by email. "The pharmacodynamics of inhaled flecainide is different."

"Inhaled flecainide converts patients to sinus rhythm at a much lower - read 'safer' - plasma concentration compared to oral or intravenous treatments," said Dr. Crijns, a cardiologist at Maastricht University Medical Center in the Netherlands. A lower concentration of flecainide is possible via inhalation because the drug is absorbed from the lungs into the pulmonary venous system, which flows to the heart's left atrium, where atrial fibrillation often occurs.

Conducted in 15 centers in Belgium and the Netherlands, the study examined 101 adult patients who had arrived at emergency departments with symptomatic atrial fibrillation starting within 48 hours of their arrival. Prospective participants were screened for their potential adverse responses, based on personal contraindications to flecainide such as heart failure, myocardial ischemia, or structural heart disease.

A flecainide acetate inhalation solution was self-administered by each patient using a nebulizer, with 10 patients inhaling a 30 mg flecainide solution, 22 inhaling a 60 mg solution, 21 inhaling 90 mg solution and 19 inhaling a 120 mg solution. A final group of 29 patients self-administered 120 mg flecainide in a solution that also contained saccharin.

The researchers obtained electrocardiograms and flecainide-blood-plasma concentrations for each patient and tracked their cardiac rhythms for four hours using a Holter monitor to record adverse events.

One-hour conversion rates back to normal rhythm increased with dosage as well as with the maximum plasma concentrations of flecainide. The percentage of patients with successful conversion were 10% in the 30 mg group, 35% in the 60 mg group, 33% in the 90 mg group, 35% in the 120 mg group and 44% in the flecainide-plus-saccharin solution.

Nearly half the patients (48%) who self-administered flecainide plus saccharin converted to sinus rhythm within 90 minutes of initiating inhalation. Half of those who reached a maximum plasma concentration greater than 200 ng/mL also converted within 90 minutes, whereas less than a quarter of patients (24%) whose maximum plasma concentration fell below 200 ng/mL obtained a normal rhythm within 90 minutes.

For most patients who returned to sinus rhythm, the conversion occurred rapidly. Across all groups, the median time to conversion was 8.1 minutes measured from the end of inhalation. Conversion led to a resolution of symptoms for 86% of these patients.

While the severity of adverse events tended to increase with dose, the majority were short-lived and mild. At the highest dose of the formulation, with saccharin included, 41% of patients reported cough, 14% reported throat pain, and 3% reported throat irritation.

Four patients had serious adverse cardiac events, deemed related to the flecainide solution because they were consistent with those observed for oral and intravenous flecainide: Two cases of transient sinus arrest, one case of atrial flutter, and one case of bradycardia. None required treatment or medication, and all resolved without further aftereffects.

Dr. Giorgio Costantino, an associate professor at the department of clinical sciences and community health at the University of Milan, in Italy, told Reuters by email that the results "could be interesting," although the findings may be due to patients spontaneously returning to sinus rhythm.

"I think that the next step should be to do a randomized control trial comparing the nasal route to the oral or intravenous route or to the standard of care," said Dr. Costantino, who has written about the treatment of atrial fibrillation in emergency departments, but was not involved in the new study.

Dr. Crijns said a randomized control trial to confirm his team's findings is being planned.

"Given the 90-minute conversion rate for inhaled flecainide (per our study result) and the well-known low placebo conversion rate within the 90-minute time frame, the formal sample size in a randomized trial would be 250 patients," Dr. Crijns said. "In the planned phase 3 trial (RESTORE -1) however, a total of 400 patients will be enrolled (or studied), and of those 300 will receive the drug and 100 the placebo."

The trial was sponsored by InCarda Therapeutics Inc., which is developing inhaled flecainide for paroxysmal AF. Several of Dr. Crijns' coauthors have financial ties to the company.

SOURCE: https://bit.ly/36v4XNn Circulation: Arrhythmia and Electrophysiology, online February 24, 2022.

By Matthew Phelan

© 2023 The Author(s). Published by Medicom Medical Publishers.
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