Disopyramide-Induced Torsade de Pointes

Multicenter study of the efficacy and safety of disopyramide in obstructive hypertrophic cardiomyopathy

“…However, the efficacy of disopyramide in ameliorating outflow gradient and heart failure symptoms has been reported only in relatively small short-term studies (16 -25). Furthermore, determining the safety of disopyramide is particularly important, given the theoretic potential for proarrhythmia in this clinical setting (26) and recognition that the natural history of HCM may be complicated by malignant ventricular arrhythmias and sudden death (3,5,27,28). Therefore, in this study it is timely to report the clinical course of 118 patients with obstructive HCM treated with oral disopyramide.…”

Practice and challenges of thorough QT studies

“…However, this might not be the most appropriate way of determining TQT study size. In crossover studies, the sample size might be the larger number of sample sizes derived from (1) and (2). In parallel TQT studies, different sizes for different treatment arms may provide a more efficient study.…”

“…42 Therefore, regulatory reviews of TQT studies routinely include a characterization of the concentrationeffect relationship. Concentration-effect modeling has been used (1) to project QT prolongation at doses not directly investigated in the TQT study, (2) to support lack of QT prolongation when the TQT study was positive based on primary statistical criteria, and (3) to confirm assay sensitivity in cases of reduced exposure to the moxifloxacin positive control. 42 A multivariate concentration-QT model was used to assess the pharmacokinetic and potential PD interaction between an investigational drug and its metabolic inhibitor.…”

“…[1][2][3] The understanding that non-antiarrhythmic drugs of practically any class can also be implicated in TdP induction is more recent, it started to be appreciated in the last decade of the previous century. Indeed, between 1991 and 2003, 6 drugs (encainide, 4 terfenadine, 5 astemazole, 6 grepafloxacin, 7 and levomethadyl 8 ) were withdrawn from marketing in the US because of the TdP risk.…”

Safety of Outpatient Initiation of Disopyramide for Obstructive Hypertrophic Cardiomyopathy Patients

“…Because of its capability to block the rapid delayed rectifier cardiac potassium current (I Kr ), it has a significant QT-prolonging effect and, as a corollary, may induce torsades de pointes (TdP). 10 This potential for proarrhythmia is the main reason for the recommendation to initiate disopyramide treatment during hospitalization. Nevertheless, over the years, this recommendation has been practiced by some HCM centers, but not by others.…”