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Drug-Induced QT/QTc Interval Shortening: Lessons from Drug-Induced QT/QTc Prolongation

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Abstract

The review discusses safety implications of drugs found to shorten the QT/QTc interval. It uses parallels with drug-induced QT/QTc prolongation. It summarizes the evidence that increases in repolarization heterogeneity are likely more important for arrhythmia induction and maintenance than the absolute changes in the QT/QTc duration. The review further compares the direct evidence of proarrhythmia caused by QT-prolonging and -shortening drugs. At present, there is little proof of QT-shortening drugs causing ventricular fibrillation in more than rare isolated instances. Comparisons of the incidence of the congenital syndromes show that short QT syndrome is much rarer than long QT syndrome, similar to the findings of short QT intervals compared with long QT intervals in the general population. Nevertheless, potential concerns come from experimental drugs developed to increase the current of potassium-rectifying channels. Some of these drugs were found to cause ventricular fibrillation in isolated hearts. Still, population exposure to drug-induced QT shortening is likely substantially lower compared with QT prolongation, especially if considering that most of the processes that decrease the so-called repolarization reserve are associated with QT prolongation. Finally, the review lists reasons why purely theoretical concepts of pharmaceutical risk cannot be used to develop regulatory guidance and concludes that at present, no additional tests and/or general acceptance restrictions are needed for the approval of QT-shortening drugs.

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Notes

  1. The acronym QT is used in this text to represent both the QT interval and the heart rate corrected QTc interval. The text makes it clear when the distinction between uncorrected QT interval and rate corrected QTc interval is necessary.

  2. Exact comparisons of this kind are always difficult. Nevertheless, the FDA summary of outpatient utilization [90] reports that from July 2009 to June 2012, lamotrigine (Lamictal XR) was dispensed to some 74,000 unique patients. This can be compared with the FDA report on sales of antibacterial drugs [91] showing 15,418 kg of moxifloxacin in 2009 alone. Thus, considering the usual doses of moxifloxacin [92], its USA use is perhaps some two magnitudes more frequent than that of lamotrigine. (Note that moxifloxacin use as a positive control in thorough QT studies makes no difference in these approximate calculations.)

  3. The 1990 FDA report of post-approval risk for drugs approved between 1976 and 1985 [132] listed terfenadine under the heading ‘No serious postapproval risks’ although the same report incorporated a QT-related warning into the label of probucol. Still, a 1984 publication on QT prolongation on probucol states “The clinical relevance of the prolongation of the QT interval induced by probucol is unclear” [133]. The first report on TdP on probucol (in a congenital long QT syndrome patient) appeared in 1989 [134, 135]. The first report on TdP on terfenadine (substantial suicidal overdose of terfenadine and astemizole) was published in 1990 [136].

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Acknowledgments

I am grateful to Nitin Joshi, the Editor-in-Chief of the Journal, for his invitation and encouragement to write this review.

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  1. St. Paul’s Cardiac Electrophysiology, University of London, NHLI, Imperial College, Dovehouse Street, London, SW3 6LY, England

    Marek Malik

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Malik, M. Drug-Induced QT/QTc Interval Shortening: Lessons from Drug-Induced QT/QTc Prolongation. Drug Saf 39, 647–659 (2016). https://doi.org/10.1007/s40264-016-0411-3

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