Drug-induced QT prolongation and torsades de pointes: evaluation of a QT nomogram

Background: Although QT prolongation is associated with increased risk of torsade de pointes (TdP), the precise relationship is not well defined. Aim: To evaluate the performance of a QT nomogram in assessing the risk of TdP from QTRR combinations. Design: Systematic review. Methods: We systematically searched MEDLINE/EMBASE for cases of drug-induced TdP. Controls were patients taking non-cardiotoxic drugs in overdose. Inclusion criteria were definite TdP, normal ECG before or after the event, association with a drug/toxin and QTRR measurements available. The upper bound of a QTRR cloud diagram developed from human preclinical studies was converted into a QT nomogram [QT vs. heart rate (HR)]. QTHR combinations for TdP cases and controls were plotted with the QT nomogram, and curves corresponding to a QTc 440 ms and QTc 500 ms for comparison (Bazetts correction). Results: We identified 129 cases of TdP. TdP cases occurred at lower HR values with longer QT intervals, with most cases occurring at HR 3090 bpm. Controls were more evenly distributed, with HR 40160 bpm. The sensitivity and specificity of the QT nomogram were 96.9 (95CI 93.999.9) and 98.7 (95CI 96.8100), respectively. For Bazett QTc 440 ms, sensitivity and specificity were 98.5 (95CI 96.3100) and 66.7 (95CI 58.674.7), respectively, whereas for Bazett QTc 500 ms they were 93.8 (95CI 89.698.0) and 97.2 (95CI 94.3100), respectively. Discussion: The QT nomogram is a clinically relevant risk assessment tool that accurately predicts arrhythmogenic risk for drug-induced QT prolongation. Further prospective evaluation of the nomogram is needed.