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Enhanced Sensitivity to Drug‐Induced QT Interval Lengthening in Patients With Heart Failure Due to Left Ventricular Systolic Dysfunction
Author(s) -
Tisdale James E.,
Overholser Brian R.,
Wroblewski Heather A.,
Sowinski Kevin M.,
Amankwa Kwadwo,
Borzak Steven,
Kingery Joanna R.,
Coram Rita,
Zipes Douglas P.,
Flockhart David A.,
Kovacs Richard J.
Publication year - 2012
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270011416939
Subject(s) - ibutilide , medicine , cardiology , qt interval , ejection fraction , interquartile range , heart failure , atrial fibrillation , sinus rhythm , torsades de pointes , quinidine , ventricular tachycardia , anesthesia
Patients with heart failure (HF) are at increased risk for drug‐induced torsades de pointes (TdP) due to unknown mechanisms. Our objective was to determine if sensitivity to drug‐induced QT interval lengthening is enhanced in patients with HF. In this multicenter, prospective study, 15 patients with atrial fibrillation or flutter requiring conversion to sinus rhythm were enrolled: 6 patients with New York Heart Association class II to III HF (mean ejection fraction [EF], 30% ± 9%), and 9 controls (mean EF, 53% ± 6%). Patients received ibutilide 1 mg intravenously. Blood samples and 12‐lead electrocardiograms were obtained prior to and during 48 hours postinfusion. Serum ibutilide concentrations at 50% maximum effect on Fridericia‐corrected QT (QT F ) intervals (EC 50 ) were determined, and areas under the effect (QT F interval vs time) curves (AUECs) were calculated. Ibutilide concentration—QT F relationships were best described by a sigmoidal E max model with a hypothetical effect compartment. Median [interquartile range] AUEC from 0 to 4 hours was larger in the HF group than in controls (1.86 [1.86–1.93] vs 1.82 [1.81–1.84] s·h; P = .04). Median EC 50 was lower in the HF group (0.48 [0.46–0.49] vs 1.85 [1.10–3.23] μg/L; P = .008). Sensitivity to drug‐induced QT interval lengthening is enhanced in patients with systolic HF, which may contribute to the increased risk of drug‐induced TdP.