ATLANTA — A new, intravenous drug for conversion of atrial fibrillation to sinus rhythm showed good efficacy and safety in a phase III trial with 265 patients.
With a few hundred patients treated so far, conversion of atrial fibrillation using RSD1235 has not led to any cases of torsades de pointes, which makes the drug more attractive than ibutilide, the only drug with Food and Drug Administration approval for conversion of atrial fibrillation, said Dr. Denis Roy, an electrophysiologist at the Montreal Heart Institute.
Cardiome and Astellas, the companies that are together developing RSD1235, are now running an additional safety study prior to submitting a new drug application to the FDA this year. RSD1235 produces a frequency-dependent blockade of sodium channels and also blocks early-repolarizing potassium channels in the atria, with little effect on ventricular electrical activity.
The efficacy study was run at 49 sites in seven countries including the United States. It enrolled patients with symptomatic atrial fibrillation or flutter that had lasted for 3 or more hours but no more than 45 days.
Patients were randomized to treatment with RSD1235 or placebo. Patients in the active-treatment arm received 3 mg/kg of RSD1235 during a 10-minute intravenous infusion, followed by a 15-minute interval and then a second infusion of 2 mg/kg that was also administered over 10 minutes. The study's primary end point was conversion to sinus rhythm for at least 1 minute at 90 minutes after treatment.
The efficacy analysis divided the 265 patients who received infusions into 240 with atrial fibrillation, 23 with atrial flutter, and 2 with an unknown baseline arrhythmia. The analysis also divided the 240 patients with atrial fibrillation into 170 patients whose arrhythmia had existed for 3 hours to 7 days, and 70 patients whose arrhythmia had lasted for 8–45 days.
In the subgroup with fibrillation for 3 hours to 7 days, treatment with RSD1235 led to sinus-rhythm conversion in 44 of 86 patients (52%), compared with conversion of 3 of 84 patients (4%), a statistically significant difference, Dr. Craig M. Pratt reported at the annual meeting of the American College of Cardiology. The median time to conversion in patients receiving RSD1235 was 8 minutes, which meant that most patients responded after they received their first dose of the drug.
The response rate was substantially less in patients whose fibrillation had lasted 8–45 days, with conversion occurring in 3 of 32 patients, a 9% rate. Overall, in all patients with atrial fibrillation in the study, treatment with RSD1235 led to sinus-rhythm conversion in 47 of 118 patients (40%), compared with conversions in 5 of 121 patients (4%) treated with placebo, said Dr. Pratt, professor of medicine at Baylor College of Medicine in Houston and director of the coronary intensive care unit at Methodist Hospital, also in Houston.
Sinus rhythm was sustained for 24 hours after treatment with RSD1235 in 98% of patients, and sinus rhythm continued for 7 days in 95% of patients in this group. RSD1235 was not effective in patients with atrial flutter.
Serious adverse effects occurred in 14 patients treated with RSD1235, and potentially drug-related serious adverse effects, including one episode of tachycardia, occurred in 3 patients. One patient with acute coronary syndrome, who should not have been enrolled in the trial, died in the RSD1235 group, Dr. Pratt said. The most common adverse effects of treatment were a metallic taste in the mouth, in 22% of patients, and sneezing in 19%.
Because of RSD1235's apparent safety compared with ibutilide, the new drug will likely become the first-line agent for chemical conversion of atrial fibrillation after it gets regulatory approval, Dr. Roy said in an interview. Dr. Roy, a coinvestigator in the study, and Dr. Pratt are both paid consultants to Cardiome and have financial relationships with Astellas. The companies also are developing an oral formulation of RSD1235 that is in phase II testing.