Drug-induced QT dispersion: does it predict the risk of torsade de pointes?

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Abstract

Drug-induced delay in ventricular repolarization and proarrhythmias have attracted considerable regulatory attention. The measure of delayed ventricular repolarization most frequently used clinically is the ability of the new chemical entity (NCE) to prolong the QTc interval on surface electrocardiogram. Before they can be approved, new chemical entities with systemic bioavailability require characterization for their potential to prolong the QTc interval. Inevitably, QTc interval prolongation has come to be recognized as a surrogate marker of the risk of torsade de pointes (TdP)—a unique form of potentially fatal polymorphic ventricular tachycardia. Although it is the best and the simplest clinical measure that is available at present, QTc interval is not a reliable surrogate of TdP. Intramyocardial dispersion of repolarization appears to play a more important role both in electrical stability of the ventricles and in arrhythmogenesis. The potential importance of myocardial dispersion of refractoriness in arrhythmogenesis has led to a number of attempts to assess it from the surface electrocardiogram.

This review summarizes the evidence for and against the predictive value of one of these attempts—measurement of the so-called QT dispersion. Although the concept of QT dispersion is the best known and most widely investigated, it has also proved to be the least successful in predicting the risks of drug-induced TdP.

Introduction

Prolongation of the QTc interval on the surface electrocardiogram (ECG) reflects the summation of delay in repolarization in all ventricular myocytes and when drug-induced, it is almost always due to inhibition of the rapid component of the delayed rectifier potassium current (IKr). The other current that is infrequently inhibited is its slow component (IKs). Drug-induced prolongation of the QTc interval, when exerted in a controlled fashion, can be antiarrhythmic but when excessive in the right setting, it can be proarrhythmic and can induce torsade de pointes (TdP), a potentially fatal and unique form of polymorphic ventricular tachycardia. One review in 1993 concluded, “At present, our knowledge base about the relation of the QT interval and torsades de pointes is grossly incomplete” [1]. Unfortunately, despite extensive research for more than a decade since, this still remains the case today.

Torsade de pointes is usually a transient tachyarrhythmia that results in palpitation. When TdP is sustained, however, there are symptoms of impaired cerebral circulation such as dizziness, syncope, and/or seizures. Because ECG recording facilities are generally not immediately available, TdP is frequently underdiagnosed. Critically, however, TdP can subsequently degenerate into ventricular fibrillation in about 20% of cases [2], often with a fatal outcome [3]. The overall mortality associated with TdP is in the order of 10% to 17% [2], [4].

It is therefore not surprising that more than any other drug-induced adverse reaction, drug-induced QT interval prolongation has been responsible in recent times for the withdrawal of many drugs from the market. These include prenylamine (used in the treatment of angina), terodiline (used for urinary incontinence), terfenadine (an H1 antihistamine), sertindole (a neuroleptic agent), astemizole (an H1 antihistamine), grepafloxacin (an antibacterial), cisapride (a gastric prokinetic drug), droperidol (a tranquilizer), and levacetylmethadol (opiate substitution therapy). Over the last decade, regulatory authorities have also rejected many new drugs or placed restrictions on the use of many old and new drugs because of concerns arising from their potential to prolong the QTc interval. There are now well over 10 antianginal and 90 noncardiovascular drugs recognized to have what has been termed the QT liability [5] and the number of such drugs continues to increase almost daily. Therefore, the relevance of investigating a new chemical entity (NCE) for its potential to delay ventricular repolarization during drug development is self-evident. The measure of delayed ventricular repolarization most frequently used is the ability of the NCE to prolong the QTc interval on surface ECG.

Although it is the best and the simplest clinical measure that is available at present, QTc interval is not a reliable surrogate of TdP. Intramyocardial spatial dispersion of repolarization appears to play a more important role both in electrical stability of the ventricles and in arrhythmogenesis, leading to a number of attempts to assess it from the surface ECG. This paper reviews the evidence for and against the clinical value of one of these attempts—the so-called QT dispersion—in predicting the clinical risk.

Section snippets

Regulatory concerns and guidance

In view of the clinical outcomes, it is not surprising that the regulatory focus on drug-induced delay in ventricular repolarization has shifted from one of a potentially desirable antiarrhythmic mechanism to that of a potentially fatal torsadogenic or proarrhythmic proclivity. Therefore, NCEs with systemic bioavailability require characterization for their potential to delay ventricular repolarization before they can be approved. Regulatory expectations of a better preapproval characterization

QT interval as a surrogate of TdP

Inevitably, QTc interval prolongation has come to be recognized as a surrogate marker of the risk of TdP, albeit an imperfect one. Although not a very reliable surrogate of TdP, the apparently all-exclusive and hitherto persuasive association between QT interval prolongation and TdP is partly the consequence of the very definition of this unique polymorphic ventricular tachyarrhythmia [12]. Ventricular tachyarrhythmias even when meeting the morphologic criteria of TdP are not labeled by many

Dispersion in repolarization vs QT dispersion

Electrophysiological studies in isolated tissues and in patients with congenital long QT syndromes (LQTS) have highlighted the role of dispersion in repolarization in induction of proarrhythmias. Evidence is gradually accumulating to show that dispersion of repolarization, rather than QT interval prolongation per se, may be the principal substrate for the development of TdP. To improve the assessment of risk, it is therefore not surprising that regulatory guidance notes underline the need to

Innovative alternatives to QT dispersion

The measurement of the QT interval is an imperfect index for the quantification of ventricular repolarization. “Duration” is only one aspect of repolarization and factors such as T wave shape, the presence of notches, or other morphologic abnormalities also carry major connotations of “abnormal” repolarization. Many carriers of LQTS gene have a normal QT interval and these individuals underscore the need for exploring other measures of abnormal repolarization. There is fairly compelling

Conclusions

Provided the ECGs recorded are technically of high quality and the intervals are measured and corrected appropriately for changes in heart rate, a number of QTc-derived parameters may be used for assessment of risk. The most reliable parameters among those easily derived are the categorical responses and population-based mean increase from baseline in placebo-corrected maximum or peak QTc interval.

Assessment of QTc interval duration, however, is only one aspect of drug-induced delay in

Acknowledgments

I wish to express my sincere appreciation to Professor Marek Malik (St George's Hospital Medical School, London, UK) for his very helpful comments and constructive discussions during the preparation of this review. Any shortcomings, however, are entirely my own responsibility.

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    The views expressed in this paper are those of the author and do not necessarily reflect the views or opinions of the MHRA, other regulatory authorities or any of their advisory bodies.

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