ACEP: Investigational Drug Converts Afib to Sinus Rhythm
BY Neil Osterweil, Senior Associate Editor, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of Pennsylvania School of Medicine.
October 16, 2006
Additional Additional Meetings Coverage
NEW ORLEANS Oct. 16 -- For converting atrial fibrillation to sinus rhythm in patients on rate-control or rhythm-control background therapy, an investigational injectable was effective rapidly for most patients, investigators reported here.
In a pooled analysis of two phase 3 clinical trials, vernakalant (RSD1235) converted atrial fibrillation to a sinus rhythm in a median 10 minutes, and nearly all patients who converted had a persistent sinus rhythm over 24 hours, reported Ian Stiell, M.D., from the University of Ottawa, in Ontario, and colleagues.
Vernakalant is a frequency-dependent Na+ and early-activating K+ channel blocker that "selectively prolongs the atrial refractory period without significantly altering ventricular refractoriness," the authors said in a poster presentation at the American College of Emergency Physicians meeting.
The randomized, double-blind, placebo controlled ACT (Atrial Arrhythmia Conversion Trials) I and III studies were designed to study the efficacy and safety of vernakalant in patients using concomitant rate- or rhythm-control medications.
In both trials, patients were stratified according to the duration of atrial fibrillation, either from more than three hours to seven days or fewer, or from more than seven days to 45 days or fewer.
The patients included men and women ages 18 and older with symptomatic atrial fibrillation or atrial flutter (patients with nontypical atrial flutter were included in ACT I). All patients were receiving adequate anticoagulant therapy, and all were hemodynamically stable, with systolic blood pressure between 90 and 160 mm Hg, and diastolic pressure lower than 95 mm Hg.
A total of 231 patients were randomly assigned to receive vernakalant at 3 mg/kg and 159 to receive placebo infused over 10 min, followed by a 15-minute observation period. If the arrhythmia did not terminate after the first infusion, a second 10-minute infusion of vernakalant at 2 mg/kg or placebo was given.
The primary efficacy outcome was the percentage of patients with treatment-induced conversion to sinus rhythm for a minimum of one minute within 90 minutes of dosing.
Background medication consisted of any rate- or rhythm-control medication taken during the week before study-drug infusion.
The safety analysis looked at adverse events, 12-lead electrocardiography, Holter monitoring, lab testing, and physical examination.
Among the patients who received vernakalant, 23% were taking rhythm-control medication (10%, class I antiarrhythmics; 7%, class III antiarrhythmics; and 8%, Betapace [sotalol]) and 67% were taking rate-control medication (52% beta blockers, 18%, calcium channel blockers, and 10%, digoxin).
Among those assigned to placebo, 23% were on rhythm-control medication (8%, class I antiarrhythmics, 6% class III antiarrhythmics, and 11% Betapace) and 73% were taking rate-control medication (53% beta blockers, 23% calcium channel blockers and 13%, digoxin).
The authors found that significantly more patients on vernakalant than on placebo converted to sinus rhythm, regardless of concomitant use of background medication (P<0.001). About half of all patients on vernakalant (51.1%) converted to a sinus rhythm, compared with 3.8% (P<0.0001).
Of those patients who converted, 78% did so after the first dose. The median time to conversion was 10 minutes.
The conversion effect of vernakalant was not affected by use of either beta blockers or calcium channel blockers.
The drug tended to be less effective in patients on either digoxin or class I or III antiarrhythmics, but more effective in patients on Betapace. These trends were not statistically significant however.
Of those patients who responded to the active drug, 97.2% were still in sinus rhythm at 24 hours, and 92.9% were still in sinus at seven days.
There were three deaths among patients with recent-onset atrial fibrillation in the vernakalant group. One of the deaths was due to ventricular fibrillation in a patient with a history of severe aortic stenosis, and was considered possibly related to the drug.
Serious adverse events (not specified) occurred in 13% of patients in each group; none of the events occurred within the first 24 hours.
The most common adverse events were metallic taste (dysgeusia) and sneezing with vernakalant during the first 24 hours and over the course of the study.
The drug's developer, Cardiome Pharma of Vancouver, and its partner, Astellas Pharma, plan to re-submit a new drug application for vernakalant. The companies received a refusal-to-file letter from the FDA in May 2006. The FDA cited in the refusal letter inconsistencies and omissions in the database submitted with the original NDA application. |
