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 QT-RR 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 QT-RR measurements available. The upper bound of a QT-RR cloud diagram developed from human preclinical studies was converted into a QT nomogram [QT vs. heart rate (HR)]. QT-HR 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 (Bazett's 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 30-90 bpm. Controls were more evenly distributed, with HR 40-160 bpm. The sensitivity and specificity of the QT nomogram were 96.9% (95%CI 93.9-99.9) and 98.7% (95%CI 96.8-100), respectively. For Bazett QTc = 440 ms, sensitivity and specificity were 98.5% (95%CI 96.3-100) and 66.7% (95%CI 58.6-74.7), respectively, whereas for Bazett QTc =500 ms they were 93.8% (95%CI 89.6-98.0) and 97.2% (95%CI 94.3-100), 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.

[1]  Dan M Roden,et al.  Drug-induced long QT and torsade de pointes: recent advances , 2007, Current opinion in cardiology.

[2]  S. Duffull,et al.  Application of pharmacokinetic-pharmacodynamic modelling in management of QT abnormalities after citalopram overdose , 2006, Intensive Care Medicine.

[3]  Lena E Friberg,et al.  Pharmacokinetic-pharmacodynamic modelling of QT interval prolongation following citalopram overdoses. , 2006, British journal of clinical pharmacology.

[4]  V. Piotrovsky,et al.  Pharmacokinetic-pharmacodynamic modeling in the data analysis and interpretation of drug-induced QT/QTc prolongation , 2005, The AAPS Journal.

[5]  Kimberly Crimin,et al.  Dynamic Beat-to-Beat Modeling of the QT-RR Interval Relationship: Analysis of QT Prolongation during Alterations of Autonomic State versus Human Ether a-go-go-Related Gene Inhibition , 2005, Journal of Pharmacology and Experimental Therapeutics.

[6]  A. Moss,et al.  Assessment of the Stability of the Individual‐Based Correction of QT Interval for Heart Rate , 2005, Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc.

[7]  Peter W Macfarlane,et al.  A comparison of commonly used QT correction formulae: the effect of heart rate on the QTc of normal ECGs. , 2004, Journal of electrocardiology.

[8]  S. Bowe,et al.  Relative Toxicity of Selective Serotonin Reuptake Inhibitors (SSRIs) in Overdose , 2004, Journal of toxicology. Clinical toxicology.

[9]  I. Whyte,et al.  Quetiapine poisoning: a case series. , 2003, Annals of Emergency Medicine.

[10]  F. Segura,et al.  QT prolongation and Torsades de Pointes in patients infected with human immunodeficiency virus and treated with methadone. , 2003, The American journal of cardiology.

[11]  G. Isbister,et al.  Bupropion Overdose: QTc Prolongation and its Clinical Significance , 2003, The Annals of pharmacotherapy.

[12]  M. Malik,et al.  Variability of heart rate correction methods for the QT interval. , 2003, British journal of clinical pharmacology.

[13]  B. Fermini,et al.  The impact of drug-induced QT interval prolongation on drug discovery and development , 2003, Nature Reviews Drug Discovery.

[14]  J. Coromilas,et al.  Amiodarone-Induced Torsade de Pointes During Bladder Irrigation: An Unusual Presentation , 2003, Angiology.

[15]  A. Camm,et al.  QT-RR relationship in healthy subjects exhibits substantial intersubject variability and high intrasubject stability. , 2002, American journal of physiology. Heart and circulatory physiology.

[16]  A. Camm,et al.  Relation between QT and RR intervals is highly individual among healthy subjects: implications for heart rate correction of the QT interval , 2002, Heart.

[17]  J. Dutcher,et al.  Torsades de pointes in 3 patients with leukemia treated with arsenic trioxide. , 2001, Blood.

[18]  Morrison Hodges,et al.  Rate Correction of the QT Interval , 1997 .

[19]  H. Kennedy,et al.  Torsades de pointes associated with drugs and toxins: recognition and management. , 1987, American heart journal.

[20]  C. Erhardt,et al.  INTERPRETATION AND USES OF MEDICAL STATISTICS , 1970 .

[21]  A J Camm,et al.  Evaluation of Drug-Induced QT Interval Prolongation , 2001, Drug safety.