Study: Inhaled Flecainide Converts Atrial Fibrillation

According to new research reported by a Massachusetts General Hospital cardiologist, an inhaled formulation of flecainide may be a safe and effective technique for the acute conversion to sinus rhythm of recent-onset atrial fibrillation (AF).

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"Atrial fibrillation is an epidemic. It's an ever-increasing problem, particularly in industrialized societies, and we need additional management options," says Jeremy Ruskin, MD, a cardiologist and cardiac electrophysiologist who is a professor of Medicine at Harvard Medical School and serves as the Omran Alomran endowed chair in Cardiology at Mass General. "One of the treatment options we lack are rapid, safe, well-tolerated drugs for converting patients quickly from atrial fibrillation to sinus rhythm. There are drugs that are used intravenously. There are drugs that are used orally. But they are resource-intensive, time-consuming, and associated with a variety of risks."

The Burden of Atrial Fibrillation

Atrial fibrillation, an irregular and often rapid heart rhythm, is linked to cardiometabolic conditions such as obesity, hypertension, diabetes, glucose intolerance, and cardiometabolic syndrome. Atrial fibrillation is associated with a significantly elevated risk for embolic stroke, congestive heart failure, cognitive impairment, and mortality.

Globally, atrial fibrillation affects an estimated 59 million people, with a lifetime risk of about 1-in-3 to 1-in-5 individuals after age 45. That risk has been steadily increasing for various reasons, including an aging population and higher rates of predisposing conditions such as hypertension, obesity, and metabolic syndrome.

Many people experiencing atrial fibrillation seek emergency care. "AF can be quite symptomatic, and the symptoms—most commonly palpitations, chest discomfort, shortness of breath, lightheadedness—can be very distressing to patients," says Dr. Ruskin. "And we lack safe and effective options for rapid conversion of atrial fibrillation in the home, so patients with acute onset AF usually present to a healthcare facility, most commonly the emergency department."

Many facilities, particularly in the United States, tend to admit patients rather than resolve the issue in the emergency department. That use of emergency departments and the resulting hospital admissions are resource-intensive and create a significant staffing and financial burden on the system, he explains.

Recent advancements, such as rapid-acting oral anticoagulants to prevent stroke, are helping to ease this burden. However, additional options that facilitate rapid conversion of atrial fibrillation to normal rhythm while the patient is in the emergency room are badly needed. Such options would allow people to be treated quickly and discharged home directly from the emergency department and avoid a substantial number of admissions.

Using Unique Formulation of Inhaled Flecainide for AF

Flecainide is a sodium channel blocker currently administered in oral and intravenous formulations for certain arrhythmias, including atrial fibrillation. It can slow the heart's electrical impulses, specifically in the atria and ventricles. While the drug is generally well tolerated in patients with AF and otherwise normal hearts, it can cause life-threatening heart rhythm abnormalities, a phenomenon known as proarrhythmia, in patients with prior heart attacks and other forms of advanced heart disease, such as congestive heart failure. Therefore, careful patient selection is important in ensuring the safe use of flecainide. In addition, the amount of drug to which the heart is exposed is an equally important determinant of proarrhythmic risk.

Dr. Ruskin believes that the inhaled formulation, by reducing the total amount of flecainide to which the patient is exposed, may reduce proarrhythmic risk while allowing sufficient drug to reach the heart to achieve rapid conversion of AF to normal sinus rhythm.

"An inhaled antiarrhythmic drug is a promising technique for achieving rapid delivery of the drug to the heart with fewer risks than those associated with IV and oral administration," he says. "Inhaled flecainide involves a lower dose. The drug is delivered directly to the lungs, and from there, it passes into the pulmonary circulation and then directly to the heart. Therefore, you get a bolus delivered directly to the heart muscle within seconds of inhalation."

In the phase II trial results recently published in JACC: Clinical Electrophysiology, Dr. Ruskin and colleagues reported on the use of inhaled flecainide in 98 patients who, under close observation, self-administered 120 mg of the treatment via nebulizer over eight minutes. All patients were monitored continuously for 90 minutes with a 12-lead Holter.

Of the 98 patients, 42.6% converted to sinus rhythm in a median of 14.6 minutes. Among the patients who converted, the average time to discharge was 2.5 hours. Only two of the patients whose AF converted experienced recurrent atrial fibrillation in the five days following conversion. The treatment was generally well tolerated, with mild and limited side effects such as cough and oropharyngeal irritation.

"With the inhaled flecainide formulation, the amount of systemic exposure is lower, and the duration of exposure is shorter, and that is likely to achieve a better safety profile," Dr. Ruskin says.

Improving the Ability to Convert Atrial Fibrillation

The preliminary data provide proof of concept, and research is now focusing on optimizing the inhalation platform to achieve improved tolerability and consistency of delivery of flecainide at doses needed to achieve higher conversion rates of AF. Dr. Ruskin says the team would like to "deliver a slightly higher dose to get slightly higher exposures with the aim of increasing the conversion rate to 50% to 60%."

The eventual hope is that a subset of patients will eventually be able to use inhaled flecainide at home for self-conversion.

"There is no one-size-fits-all treatment for atrial fibrillation, and from a public health standpoint, the ultimate goal is to reduce the global burden of atrial fibrillation by reducing the epidemic of risk factors that are widely prevalent in the general population," he says. "In the meantime, what we're hoping for is another, hopefully, more efficient, safe, and effective option for the acute care of patients with recurrent atrial fibrillation who currently suffer from a range of symptoms and risks and whose care imposes a significant resource and financial burden on the healthcare system."

Learn more about the Telemachus & Irene Demoulas Family Foundation Center for Cardiac Arrhythmias

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