QT Prolongation: Closing in on the Target of Meaningful Data

Experts provide an update on a troublesome (and notorious) cardiac safety issue
Jun 01, 2005

A new study in Holland suggests that yet another group of antipsychotic and gastrointestinal treatments have been linked to increased risk of sudden cardiac death. In a longitudinal study by doctors from seven medical centers in the Netherlands, Thorazine (chlorpromazine), Haldol (haloperidol), and Orap (pimozide)—as well as two gastrointestinal drugs, Propulsid (cisapride) and Motilium (domperidone)—have been linked to increased risk of irregular heartbeat.

Like many medications before them, these drugs have been shown to prolong the QT interval, the few hundred milliseconds of electrical activity that control the heart's pumping action. QT prolongation has become a significant concern for pharma and FDA since the early 1990s, when Seldane (terfenadine), a popular antihistamine headed for OTC status, was derailed by data that linked it with sudden cardiac death and life-threatening ventricular tachyarrhythmias, such as Torsades de Pointes (TdP). In the years since, an increasing number of drugs—antihistamines, antipsychotics, antidepressants, and antibacterials—have been given additional warnings or pulled from the market because they increased the QT interval.

QT prolongation is not likely to go away as an issue for the pharmaceutical industry. In 2001, FDA's Janet Woodcock told the Los Angeles Times that the agency had lost patience with drugs that caused it. "We're encouraging people, if there's QT prolongation, don't develop it," she said.

It is increasingly important for pharma researchers to understand what QT prolongation is and how it affects clinical development and drug safety.

What is the QT interval?

Cardiac Cycle
The QT interval is part of the cardiac cycle as it is represented on paper with an electrocardiograph (ECG or EKG). The cardiac cycle—a single heartbeat—starts when the atria begin to fill with blood, and ends when the ventricles recover from the contraction that propels blood throughout the body.

An ECG represents the heartbeat as a series of waves that measure electrical changes in the walls of the heart—depolarization and repolarization—that accompany the blood movement. The QT interval is the time, in milliseconds, between the depolarization (Q) at the onset of ventricular contraction and the repolarization (T) that prepares for another contraction.

What is the normal QT interval?

The normal QT interval varies with the heart rate. That's why the QT interval is corrected for what it would be theoretically, at a rate of 60 beats per minute. This is known as the QTc (corrected QT interval). The normal QTc generally is accepted to be less than 440 ms, and on average is slightly longer in females. FDA concept papers have mentioned normal QTc as:

  • <430 ms in males and <450 ms in females
  • borderline between 430 and 450 ms for males and between 450 and 470 ms for females.

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