A M Choy1, D Darbar, S Dell'Orto, D M Roden. 1. Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602, USA.
Abstract
OBJECTIVES: The purpose of this study was to test the hypothesis that the extent of drug-induced QT prolongation by dofetilide is greater in sinus rhythm (SR) after cardioversion compared with during atrial fibrillation (AF). BACKGROUND: Anecdotes suggest that when action potential-prolonging antiarrhythmic drugs are used for AF, excessive QT prolongation and torsades de pointes (TdP) often occur shortly after sinus rhythm is restored. METHODS: QT was measured in nine patients with AF who received two identical infusions of dofetilide: 1) before elective direct current cardioversion and 2) within 24 h of restoration of SR. RESULTS: During AF, dofetilide did not prolong QT (baseline: 368 +/- 48 ms vs. drug: 391 +/- 60, p = NS) whereas during SR, QT was prolonged from 405 +/- 55 to 470 +/- 67 ms (p < 0.01). In four patients (group I), the SR dofetilide infusion was terminated early because QT prolonged to >500 ms, and one patient developed asymptomatic nonsustained TdP. The remaining five patients (group II) received the entire dose during SR. Although deltaQT was greater in group I during SR (91 +/- 22 vs. 45 +/- 25 ms, p < 0.05), plasma dofetilide concentrations during SR were similar in the two groups (2.72 +/- 0.96 vs. 2.77 +/- 0.25 ng/ml), and in AF (2.76 +/- 1.22 ng/ml). DeltaQT in SR correlated inversely with baseline SR heart rate (r = -0.69, p < 0.05), and QT dispersion developing during the infusion (r = 0.79, p < 0.01). CONCLUSIONS: Shortly after restoration of SR, there was increased sensitivity to QT prolongation by this I(Kr)-specific blocker. Slower heart rates after cardioversion and QT dispersion during treatment appear to be important predictors of this response.
OBJECTIVES: The purpose of this study was to test the hypothesis that the extent of drug-induced QT prolongation by dofetilide is greater in sinus rhythm (SR) after cardioversion compared with during atrial fibrillation (AF). BACKGROUND: Anecdotes suggest that when action potential-prolonging antiarrhythmic drugs are used for AF, excessive QT prolongation and torsades de pointes (TdP) often occur shortly after sinus rhythm is restored. METHODS: QT was measured in nine patients with AF who received two identical infusions of dofetilide: 1) before elective direct current cardioversion and 2) within 24 h of restoration of SR. RESULTS: During AF, dofetilide did not prolong QT (baseline: 368 +/- 48 ms vs. drug: 391 +/- 60, p = NS) whereas during SR, QT was prolonged from 405 +/- 55 to 470 +/- 67 ms (p < 0.01). In four patients (group I), the SR dofetilide infusion was terminated early because QT prolonged to >500 ms, and one patient developed asymptomatic nonsustained TdP. The remaining five patients (group II) received the entire dose during SR. Although deltaQT was greater in group I during SR (91 +/- 22 vs. 45 +/- 25 ms, p < 0.05), plasma dofetilide concentrations during SR were similar in the two groups (2.72 +/- 0.96 vs. 2.77 +/- 0.25 ng/ml), and in AF (2.76 +/- 1.22 ng/ml). DeltaQT in SR correlated inversely with baseline SR heart rate (r = -0.69, p < 0.05), and QT dispersion developing during the infusion (r = 0.79, p < 0.01). CONCLUSIONS: Shortly after restoration of SR, there was increased sensitivity to QT prolongation by this I(Kr)-specific blocker. Slower heart rates after cardioversion and QT dispersion during treatment appear to be important predictors of this response.
Authors: Russell A Wilke; Debbie W Lin; Dan M Roden; Paul B Watkins; David Flockhart; Issam Zineh; Kathleen M Giacomini; Ronald M Krauss Journal: Nat Rev Drug Discov Date: 2007-11 Impact factor: 84.694
Authors: Anne S Y Chain; Jeanne P Dieleman; Charlotte van Noord; Albert Hofman; Bruno H Ch Stricker; Meindert Danhof; Miriam C J M Sturkenboom; Oscar Della Pasqua Journal: Br J Clin Pharmacol Date: 2013-12 Impact factor: 4.335
Authors: Dawood Darbar; John Kimbrough; Asif Jawaid; Robert McCray; Marylyn D Ritchie; Dan M Roden Journal: J Am Coll Cardiol Date: 2008-02-26 Impact factor: 24.094