New Orleans, LA - A new, fast-acting, acute-use intravenous antiarrhythmic agent has been shown to be efficacious in the treatment of atrial fibrillation. The drug, known as RSD1235 (Cardiome Pharma Corp, Vancouver, BC), successfully converted more patients to normal sinus rhythm than placebo and was shown to be safe and well tolerated, with no documented cases of drug-related torsades de pointes.

Presenting the results of the late-breaking clinical trial at the Heart Rhythm Society 2005 Scientific Sessions, lead investigator Dr Dennis Roy (Montreal Heart Institute, QC) told heartwire that the drug differs from other antiarrhythmic agents in that it selectively prolongs atrial refractory periods.

"It is an interesting drug because it differs in its basic electrophysiological properties," said Roy. "It has very selective atrial activity, with electrophysiological changes that are almost exclusive to the atrium, and with very little effect on the ventricle. This makes it effective in attacking atrial arrhythmias without causing proarrhythmia or ventricular arrhythmias."

Roy presented the data from Atrial Arrhythmia Conversion Trial I (ACT I), a randomized, double-blind, placebo-controlled study conducted in North America and Europe. The trial enrolled 356 patients 18 years of age and older with ECG-documented atrial fibrillation that developed within three hours to 45 days. Patients were hemodynamically stable and treated with anticoagulation therapy as outlined by current guidelines.

The primary end point of the study was the conversion of atrial fibrillation to sinus rhythm within 90 minutes of RSD1235 initiation in patients with recent-onset atrial fibrillation (within the last three hours to seven days). Secondary end points included the conversion to normal sinus rhythm in patients with atrial fibrillation of longer duration (developing within three hours to 45 days and eight days to 45 days).

ACT I: Efficacy results

Atrial fibrillation patients	RSD1235	Placebo	p
Conversion rate (%) in recent-onset atrial fibrillation patients (3 h-7 d)*	52	4	<0.0001
Conversion rate (%) in patients with longer duration atrial fibrillation (3 h-45 d)	38	3	<0.0001
Conversion rate (%) in patients with longer duration atrial fibrillation (8 d-45 d)	8	0	0.092

RSD1235 successfully converted atrial fibrillation to normal sinus rhythm, with the drug terminating the arrhythmia in more than half of patients with recent-onset atrial fibrillation. Most patients, 76%, responded to the first dose of therapy, and nearly all patients were still in sinus rhythm at 24 hours. The median time to conversion was rapid, occurring within 11 minutes. "That's pretty fast," said Roy. "This would get the patients out of the emergency room pretty quickly."

Investigators report that the drug was safe and well tolerated by patients. There were no reported cases of torsades de pointes related to the study drug. At 30 days, a majority of the serious adverse events related to RSD1235 were cardiac in nature, mainly the recurrence of atrial fibrillation. The most common adverse events reported during the first 24 hours were taste impairment (30%), paresthesia (11%), and sneezing (16%).

Serious adverse events at 30 days

Serious adverse events	Placebo (n=115)	RSD1235 (n=221)
Overall serious adverse events, n (%)	21 (18.3)	29 (13.1)
Serious cardiac events, n (%)	17 (14.8)	22 (10.0)

Speaking with heartwire, Roy said the data on RSD1235 look promising and the drug could provide an option in the acute treatment of atrial fibrillation. At present, the few antiarrhythmic drugs available are not very effective, said Roy.

"The most obvious drug that we can compare it to at the moment is ibutilide, which underwent similar clinical investigation a few years ago," he added. "At the moment it is the only officially approved drug for the conversion of atrial fibrillation. Ibutilide has a conversion ratio of about 35%. RSD1235 has a conversion ratio of about 50% to 60%, depending on the study population, making it a superior agent for conversion. Ibutilide also has a risk of torsades de pointes of about 4%. In this light, RSD1235 looks much better."

Roy said the drug would likely be used for the acute conversion of atrial fibrillation in the emergency room. The drug is currently being studied in the postoperative setting, where investigators believe it might also be successful converting surgery patients in atrial fibrillation to normal sinus rhythm.