Abstract & Commentary
Synopsis: RSD1235 shows promise as an agent for the management of atrial fibrillation.
Source: Roy D, et al. J Am Coll Cardiol. 2004;44: 2355-2361.
RSD1235 is a new antiarrhythmic compound that has unusual electrophysiologic properties. It is a mixed frequency-dependent sodium channel and an atrial-preferential potassium channel blocker. In animal models it has been effective in terminating and preventing recurrence of atrial fibrillation. In preclinical trials and in studies on normal volunteers, the drug has not been shown to have effects on ventricular refractoriness or the QT interval. This study examines the efficacy of intravenous infusions of RSD1235 for terminating recent onset atrial fibrillation.
Patients were eligible for the study if they had persistent atrial fibrillation with a duration between 3 and 72 hours at the time of randomization. Anticoagulation was managed in accordance with current guidelines. Patients were required to be hemodynamically stable. The major exclusion criteria included prolongation of the QT interval or QRS duration, recent unstable cardiac disease (ischemia, heart failure, or surgery), reversible causes of atrial fibrillation, concurrent treatment with known QT prolonging drugs or class I or class III antiarrhythmic drugs, electrolyte imbalance or significant renal or hepatic dysfunction. Preenrollment treatment with rate control agents was permitted.
Patients were randomized to one of 3 groups. Each group received 1 or 2 10-minute intravenous transfusions with a 30 minute interval between the 2 infusions. The infusions were either placebo followed by placebo, RSD1235 0.5 mg per kg followed by 1.0 mg/kg, if required and RSD1235 2.0 mg/kg followed by 3.0 mg/kg, if required. The primary efficacy end point was termination of atrial fibrillation. Secondary end points included the number of patients who remained in sinus rhythm, at 0.5, 1, and 24 hours after the end of the last infusion and the time to conversion of sinus rhythm after first exposure to study drug. Patients in whom atrial fibrillation persisted 1 hour after the end of the last infusion could be electrically cardioverted.
During the infusion, the patient was monitored continuously. The infusion could be discontinued if the patient developed either hypotension or hypertension, significant bradycardia, or other conduction abnormalities.
A total of 56 patients were enrolled, randomized, and received study drug. There was no significant difference in clinical characteristics between the 3 groups. The mean duration of atrial fibrillation was less than 24 hours in all 3 groups.
The cumulative AF termination rate within 30 minutes after the last infusion was 61% in the high dose RSD1235 group, 11% in the low dose RSD1235 group, and 5% in the placebo group. Of the 11 terminations in the high-dose RSD1235 group, 10 of 18 patients converted to sinus rhythm, and one converted into atrial flutter. The median time to termination of atrial fibrillation was 11 minutes after the start of the first infusion. All patients who converted did so within 10 minutes of the end of the last infusion. One patient in the high dose RSD1235 group went back into atrial fibrillation by 1 hour after infusion. RSD1235 did not significantly prolong the QTc or the QRS intervals at either high or low dose. In the high-dose RSD1235 group, the predrug QTc at baseline was 434 ± 7 m/sec. At the end of the first infusion, it was 449 ± 9 m/sec, and at the end of the second infusion, it was 447 ± 17 m/sec. There were no clinically significant changes from baseline systolic blood pressure within groups or between groups. Two patients developed hypotension in the placebo group, and 1 case of transient hypotension was noted in the high-dose RSD1235 group. No episodes of significant AV block during atrial fibrillation or sinus bradycardia were noted.
There were 4 mild adverse events reported by 2 RSD1235 patients that were thought to be either definitely or probably study drug related. One patient reported paresthesias and 1 patient reported paresthesia, nausea, and hypotension. Episodes of nonsustained ventricular tachycardia and frequent ventricular premature beats were seen with some frequency in all 3 groups.
However, no patient developed torsade de pointes, sustained ventricular tachycardia, or ventricular fibrillation in response to the drug infusion. Several complications were, however, noted with electrical cardioversion. One placebo patient developed a transient cerebral ischemic attack 24 hours after electrical cardioversion, despite a therapeutic prothrombin time. Severe bradycardia with hypotension immediately after electrical conversion, pulmonary edema, and recurrent atrial fibrillation each occurred in 1 placebo patient. One patient in the low-dose RSD1235 group developed ventricular fibrillation when he received an asynchronous electrical shock during a cardioversion attempt.
Plasma levels of RSD1235 were measured. The median plasma level at the time of atrial fibrillation conversion was 1.3 m/mL. The mean terminal elimination half life of the drug after infusion was 3.1 hours.
Roy et al conclude that RSD1235 shows promise as an agent for the management of atrial fibrillation. In this acute conversion study, it was not associated with any drug induced proarrhythmia or serious adverse events.
Comment by John P. DiMarco, MD, PhD
Pharmacologic therapy for atrial fibrillation has often been limited by the ventricular proarrhythmic effects of antiarrhythmic drugs. It has, therefore, been a goal of pharmacologists to develop agents that would specifically affect atrial electrophysiology. RSD1235 is a new agent developed by Cardiome Pharma which seems to have a favorable electrophysiologic profile in that it blocks frequency dependent sodium channels and potassium channels only in the atrium.
Studies on the termination of atrial fibrillation are highly dependent upon the patient population studied. When studies are carried out in patients with very recent onset atrial fibrillation (less than 48-78 hours), relatively high spontaneous conversion rates over a 12-24 hour period may be seen. In atrial fibrillation of longer than 3 days duration, both spontaneous and pharmacologic conversion rates are expected to be much lower. In this study, Roy and colleagues used a short period of observation to measure drug effect. Because of this, the conversion rates on both placebo and after a subtherapeutic dose of RSD1235 were quite low. A significant drug effect in the high dose group was clearly demonstrated.
This relatively high acute conversion rate, combined with the absence of effects on the QT interval and the QRS duration, make RSD1235 a promising agent worthy of further investigation. The drug’s short half life is favorable for intravenous conversions but would hamper oral therapy. However, if an oral preparation could be developed and be shown to be safe, RSD1235 could be used for both outpatient self-administration, as well as possibly for chronic prevention of recurrence. The absence of untoward effects on the ventricle, if confirmed in further studies, would make RSD1235 safe for unmonitored, outpatient loading and for chronic prophylactic use.
Dr. DiMarco, Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville, is on the Editorial Board of Clinical Cardiology Alert.