Prediction of Torsades de Pointes from QT interval: analysis of a case series with amisulpride
Coulter CV,1 Joy JP,1 Duffull SB,1 Isbister GK2
1School of Pharmacy, University of Otago, Dunedin, New Zealand 2Department of Clinical Toxicology, Calvary Mater Newcastle Hospital, Newcastle, Australia
Background and objectives: Torsades de Pointes (TdP) is a potentially fatal ventricular arrhythmia that is associated with a drug-induced QT prolongation. Despite numerous methods to assess the risk of TdP based on the presence of QT prolongation few studies have investigated the importance of the magnitude of QT prolongation and the risk of TdP. In addition, previous studies have generally provided data on a wide spectrum of drugs and therefore confound the causal relationship of the magnitude of QT interval prolongation with the inherent cardiotoxicity of the drug. The objective of this study was to assess whether the magnitude of QT prolongation is a better predictor of TdP than dose alone in a series of amisulpride poisonings.
Methods: The study included 457 ECGs from 86 patients with amisulpride overdoses who ingested a median dose of 6 g (range: 1.2 g to 120 g). The QT interval was manually measured on each ECG using a standardised method. The QT interval was measured in 3 chest and 3 limb leads and the median was calculated. For cases of TdP the longest QT interval was chosen that occurred prior to the episode of TdP, and for controls the longest QT interval was selected over the entire admission period. For each ECG the following measurements of QT were used: the absolute QT, corrected QT values using Bazett’s formula [QTcB] and Fredericia’s formula [QTcF], and the orthogonal QT interval defined as the shortest distance of the QT-HR [HR = heart rate] pair from the “at risk” line on the QT-nomogram, termed orthogonal distance (OD). Logistic regression using NONMEM (version 6) was performed to investigate the association between dose, RR interval, and the various measurements of the QT interval, on the probability of TdP.
Results: TdP occured in 8 (9.3%) of the patients. The dose of amisulpride in these patients ranged from 4g to 80g. Both dose and RR interval improved the prediction of TdP over and above simply the presence of a prolonged QT interval. All four QT measures, the absolute QT, QTcB, QTcF, and OD, were superior to both dose and HR interval. No metric proved superior than any other. Conclusions: For all QT measures, QT, QTcB, QTcF, and OD, the extent of the prolongation was a useful predictor of TdP compared to dose. The different QT measures were indistinguishable from each other.
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