Safety and efficacy of flecainide in subjects with long QT-3 syndrome (ΔKPQ mutation):: A randomized, double,blind, placebo-controlled clinical trial

Background: We conducted a study of chronic therapy with flecainide versus placebo in a small group of LQT-3 patients with the Delta KPQ deletion to evaluate the safety-and efficacy of flecainide in this genetic disorder. In vitro studies have shown that flecainide provides correction of the impaired inactivation associated with the Delta KPQ deletion. Methods: A randomized, double-blind, placebo-controlled clinical trial was conducted with flecainide and placebo in six male LQT-3 subjects with the Delta KPQ deletion. Results: The lowest possible dose of flecainide associated with at least a 40 ms reduction in the QTc interval was determined in an initial open-label, dose-ranging investigation using one-fourth or half of the recommended maximal antiarrhythmic flecainide dose. QTc reduction was achieved with a flecainide dose of 1.5 mg/kg per day in 4 subjects and with 3.0 mg/kg per day in 2 subjects. Subjects were randomized to four 6-month alternating periods of flecainide and placebo therapy based on the open-label dose findings. Average QTc values during placebo and flecainide therapies were 534 ms and 503 ms, respectively, with an adjusted reduction in QTc of -27.1 ms (95% confidence interval: -36.8 ms to -17.4 ms; P < 0.001) at a mean flecainicle blood level of 0.11 +/- 0.05 ng/ml. Minimal prolongation in QRS occurred (mean: +2.5 ms), and there were no major adverse cardiac effects. Conclusions: Chronic low-dose flecainicle significantly shortens the QTc interval in LQT-3 subjects with the Delta KPQ mutation. No major adverse drug effects were observed with flecainide during this trial, but the sample size is not large enough to evaluate the safety of flecainicle therapy in patients with this mutation.