QT as a marker for Torsade de Pointes

Several drugs were withdrawn from the market during the last twenty-five years due to an increased risk of a potentially lethal ventricular tachycardia called “Torsade de Pointes” (twisting of the points).   The development of this arrhythmia is preceded by the prolongation of the QT interval in the electrocardiogram (ECG). The following article will provide a brief overview of the QT interval and its relationship to Torsade de Pointes (TdP).

QT interval definition:

The interior of the resting cardiac cell has a negative electrical charge relative to the surrounding area.   Cardiac muscle contraction is triggered by depolarization, or development of positive charge within the cardiac cells. This active phase needs to be followed by a recovery phase, or repolarization, to return the resting negative membrane potential.  This rapid change in cellular charge is due to influx and efflux of charged ions through ion channels in the cell wall.   If the repolarization is slow due to ion channel dysfunction, the QT interval can be prolonged.

The cardiac electric activity is recorded on an ECG. Several waveforms are displayed on such tracings: the P wave corresponds to the atrial depolarization; the QRS corresponds to the ventricular depolarization; and the T wave corresponds to the ventricular repolarization. The QT interval is measured from the beginning of the QRS to the end of the T wave.       

QT as a surrogate marker:

Congenital Long QT Syndrome (LQTS) has served as a model for drug-induced QT prolongation and TdP. The study of LQTS patients has revealed that the QT interval prolongation is due to genetic ionic channel alterations. Furthermore, there is a statistical correlation between QT interval duration and mortality in several other patient populations.

Drugs that cause QT prolongation and TdP impair ion channel function in a manner similar to abnormal channel function seen in LQTS.  Almost all of the QT prolongation and TdP induced by the drugs is caused by the blockade of a specific potassium channel involved with repolarization, the Ikr channel.  Some times this channel is called the hERG channel for the initial description of the gene that codes for it.    In general, the more the QT interval is prolonged, the higher the risk of TdP., although, there are notable exceptions such as amiodarone.

In addition, in most episodes of drug-induced TdP, there are multiple factors involved that increase the risk such as underlying heart disease, metabolic inhibitors, and combination with other compounds that cause QT interval prolongation. This is the so-called “Perfect Storm” scenario.

Because of several withdrawals of marketed drugs after extensive patient exposure, a dialogue to develop a prospective approach to detecting QT interval prolongation began in 1997 when the European Committee for Proprietary Medicinal Products issued the first regulatory document that focused on QT risk assessment.  This document formed the basis for several later regulatory documents that ultimately evolved into ICH E14, released in 2005.

ICH E14 advocates a “Thorough QT/QTc” study for essentially all new compounds to assess the risk of QT prolongation.  A Thorough QT/QTc is usually performed in a randomized, double-blinded manner in healthy volunteers.  In addition to placebo, there is an active control that causes a known amount of QT interval prolongation to serve as a calibration of the study.  In addition, the compound is usually given at both a therapeutic and supratherapeutic dose.  The supratherapeutic dose is meant to mimic exposures that might be seen in patients with liver disease, with the use of metabolic inhibitors of the compound, or in combination with other compounds that might prolong the QT interval. A drug that does not cause significant QT prolongation at high doses in healthy volunteers would be less likely to cause TdP in patients.

The limitation of the use of prolongation of the QT interval as a marker of risk for TdP is widely recognized.  Several other biomarkers examining a variety of aspects of the T wave morphology are currently under active investigation.  In the mean time, QT interval prolongation assessment remains the mainstay in assessing risk for drug-induced TdP.

Conclusion:
Drug-induced TdP remains a significant drug development problem.  The best current assessment of this risk is through the “Thorough QT/QTc” study advocated in ICH E14, but newer biomarkers are being actively investigated.  With very few exceptions, all drugs will require a “Thorough QT/QTtc” study.

For more information:

Bill Wheeler, MD, FACC
Medical Director
Centralized Cardiac Services

Benoit Tyl, MD
Medical Director Europe
Centralized Cardiac Services