Electrocardiographic and Clinical Predictors of Torsades de Pointes Induced by Almokalant Infusion in Patients with Chronic Atrial Fibrillation or Flutter: A Prospective Study

Houltz, Birgitta; Darpö, Börje; Edvardsson, Nils; Blomström, Per; Brachmann, Johannes; Crijns, Harry J.G.M.; Jensen, Steen M.; Svernhage, Elisabeth; Vallin, Hans; Swedberg, Karl

doi:10.1111/j.1540-8159.1998.tb00150.x

Cited by 105 publications

(54 citation statements)

References 36 publications

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“…This assumption is also supported by a clinical study with the I Kr -blocking class III agent almokalant, in which it was demonstrated that an increased instability of QT characterized patients who subsequently developed TdP. 32 If instability also commonly precedes proarrhythmia in patients who are sensitive to proarrhythmia induced by class III agents, then it might be possible to recognize some of the vulnerable patients by careful electrophysiological monitoring during their initial treatment. Similarly, if the electrophysiological substrate changes during therapy, instability of QT might provide a warning for impending proarrhythmia problems.…”

Section: Discussionmentioning

confidence: 62%

Instability and Triangulation of the Action Potential Predict Serious Proarrhythmia, but Action Potential Duration Prolongation Is Antiarrhythmic

2001

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Background-Prolongation of action potential duration (APD) is considered a major antiarrhythmic mechanism (class III), but paradoxically, it frequently is also proarrhythmic (torsade de pointes). Methods and Results-The cardiac electrophysiological effects of 702 chemicals (class III or HERG channel block) were studied in 1071 rabbit Langendorff-perfused hearts. Temporal instability of APD, triangulation (duration of phase 3 repolarization), reverse use-dependence, and induction of ectopic beats were measured. Instability, triangulation, and reverse use-dependence were found to be important determinants of proarrhythmia. Agents that lengthened the APD by Ͼ50 ms, with induction of instability, triangulation, and reverse use-dependence (nϭ59), induced proarrhythmia (primarily polymorphic ventricular tachycardia); in their absence (nϭ19), the same prolongation of APD induced no proarrhythmia but significant antiarrhythmia (PϽ0.001). Shortening of APD, when accompanied by instability and triangulation, was also markedly proarrhythmic (primarily monomorphic ventricular tachycardia). In experiments in which instability and triangulation were present, proarrhythmia declined with prolongation of APD, but this effect was not large enough to become antiarrhythmic. Only with agents without instability did prolongation of APD become antiarrhythmic. For 20 selected compounds, it was shown that instability of APD and triangulation observed in vitro were strong predictors of in vivo proarrhythmia (torsade de pointes). Conclusions-Lengthening of APD without instability or triangulation is not proarrhythmic but rather antiarrhythmic.

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Section: Discussionmentioning

confidence: 62%

Instability and Triangulation of the Action Potential Predict Serious Proarrhythmia, but Action Potential Duration Prolongation Is Antiarrhythmic

2001

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“…Recently, it has been demonstrated that in patients who developed TdP secondary to class III agents, druginduced QTc prolongation was more marked than in patients without TdP and, furthermore, it was not related to the dose of the drug [34] . Thus, patients with TdP showed an abnormal response following exposure to the drug.…”

Section: Policy Conference 1217mentioning

confidence: 99%

The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a Policy Conference of the European Society of Cardiology

Haverkamp¹,

Breithardt²,

Janse³

et al. 2000

European Heart Journal

410

273

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The scientific and clinical basis of drug-induced QT prolongation and proarrhythmia was summarized by formal presentations. The speakers were chosen for their particular competence in the relevant field. Furthermore, selected topics were discussed in detail in separate workshops. This document represents the executive summary of the Conference. It is based on written reports composed by the speakers and the chairs of the workshops. Before preparation of the final version of the document, a draft was circulated to all participants of the Conference for suggestions and comments. The opinions expressed in this document are those of the participants and do not necessarily reflect the official position of their organisations or agencies. The meeting was made possible by unrestricted educational grants to the Committee for Scientific and Clinical Initiatives of the ESC from several companies listed in the Appendix. The problemQT interval prolongation, and possibly increased QT dispersion, are risk factors in a number of cardiovascular as well as non-cardiovascular diseases. A variety of drugs prolong the QT interval, although the major examples are the so-called class III antiarrhythmics. These drugs generally exert their therapeutic effect by affecting potassium ion channels, thereby reducing outward, repolarizing current, and prolonging action potential duration and the QT interval. Many of these drugs have been developed for conversion of atrial fibrillation and/or maintenance of sinus rhythm in patients with recurrent atrial fibrillation. Such patients are at low risk of potentially fatal arrhythmias, at least in the absence of antiarrhythmic drug therapy.However, antiarrhythmic drugs which prolong cardiac repolarization are not harmless, as they may induce

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“…In contrast, QT interval dispersion did not increase in 29 patients who received class IA antiarrhythmic drugs but did not develop Torsades de Pointes. Similarly, Houltz et al, 11 using all 12 ECG leads, found that QT interval dispersion was significantly greater in 6 patients with atrial fibrillation who developed Torsades de Pointes caused by the class III antiarrhythmic agent almokalant compared with 94 patients who did not.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Intravenous Haloperidol on QT Interval Dispersion in Critically Ill Patients: Comparison with QT Interval Prolongation for Assessment of Risk of Torsades de Pointes

Tisdale

Rasty

Padhi

et al. 2001

The Journal of Clinical Pharma

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The objective of this study was to determine the effect of intravenous haloperidol on QT interval dispersion in critically ill patients and to compare increases in QT interval dispersion and QTc intervals in patients who developed haloperidol‐induced Torsades de Pointes versus those in patients who did not. This was a case‐controlled study of 30 critically ill patients who received intravenous haloperidol for delusional agitation. Cases were patients (n = 6) who developed Torsades de Pointes during haloperidol therapy. Controls were patients (n = 24) who did not experience haloperidol‐induced Torsades de Pointes. QTc intervals were measured and QT interval dispersion was calculated. Haloperidol prolonged QTc interval compared to pretreatment values in Torsades de Pointes patients (606 ± 61 ms vs. 501 ± 44 ms, p = 0.007) by a greater magnitude than in patients who did not experience Torsades de Pointes (507 ± 60 ms vs. 466 ± 44, p = 0.01). Twelve‐lead analysis revealed that QTinterval dispersion increased in patients who experienced Torsades de Pointes (from 63 ± 11 to 95 ± 22 ms, p = 0.03) but not in those who did not (62 ± 18 vs. 60 ± 26 ms, p = 0.66). Analysis of precordial leads only showed no significant haloperidol‐associated increases in QT interval dispersion in either group. The odds of developing haloperidol‐induced Torsades de Pointes were highest in patients with QTc interval > 521 ms during haloperidol therapy (odds ratio = 12.0). It was concluded that intravenous haloperidol prolongs QTc intervals in critically ill patients. The degree of prolongation is greater in patients who experience Torsades de Pointes. QT interval dispersion may be increased in patients who develop haloperidol‐induced Torsades de Pointes compared with those who do not. However, these effects are dependent on the method of measurement (12 leads vs. precordial leads). In addition, the odds of haloperidol‐induced Torsades de Pointes are higher in patients with QTc interval prolongation compared with increased QTinterval dispersion. Therefore, QTc inter‐val determination remains preferable to QT interval dispersion as a means assessment of risk for haloperidol‐induced Torsades de Pointes.

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Electrocardiographic and Clinical Predictors of Torsades de Pointes Induced by Almokalant Infusion in Patients with Chronic Atrial Fibrillation or Flutter: A Prospective Study

Cited by 105 publications

References 36 publications

Instability and Triangulation of the Action Potential Predict Serious Proarrhythmia, but Action Potential Duration Prolongation Is Antiarrhythmic

Instability and Triangulation of the Action Potential Predict Serious Proarrhythmia, but Action Potential Duration Prolongation Is Antiarrhythmic

The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a Policy Conference of the European Society of Cardiology

The Effect of Intravenous Haloperidol on QT Interval Dispersion in Critically Ill Patients: Comparison with QT Interval Prolongation for Assessment of Risk of Torsades de Pointes

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