Bazett and Fridericia QT correction formulas interfere with measurement of drug-induced changes in QT interval

Julia H Indik, Ellen C. Pearson, Karen Fried, Raymond L. Woosley

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

Background: The QT interval on the ECG is prolonged by more than 50 marketed drugs, an effect that has been associated with syncope and/or sudden cardiac death due to an arrhythmia. Because changes in heart rate also change the QT interval, it has become standard practice to use a correction formula, such as the Bazett formula, to normalize the QT interval to a heart rate of 60 bpm, that is, the rate-corrected QT or QTc. Numerous other formulas have been devised to make this correction, including the Fridericia, Hodges, and Framingham formulas. Objectives: The purpose of this study was to investigate how the Bazett formula and three other formulas influence assessment of the QT-prolonging effect of the potassium channel-blocking drug ibutilide. Methods: Using a standardized physical activity protocol, the QT interval was assessed over a broad range of heart rates before and after an infusion of ibutilide (4.75 μg/kg) that produced a stable 15- to 20-ms QT prolongation in consenting normal subjects (9 men and 9 women). The QT interval was measured digitally over a range of heart rates from 60 to 120 bpm, and then four correction formulas (Bazett, Fridericia, Framingham, or Hodges) were applied. The uncorrected change in QT interval due to ibutilide was compared with the change using each of the formulas by repeated measures analysis of variance. Results: At heart rates from 60 to 120 bpm, the Bazett and Fridericia correction formulas overestimated the change in QT in both men and women (P <.001). However, the Framingham and Hodges formulas did not alter the accuracy of the assessment of QT interval change. Conclusion: Rate correction of QT intervals using the standard Bazett and Fridericia formulas can introduce significant errors in the assessment of drug effects on the QT interval. This has implications for the clinical assessment of drug effects and for the safety assessment of new drugs under development.

Original languageEnglish (US)
Pages (from-to)1003-1007
Number of pages5
JournalHeart Rhythm
Volume3
Issue number9
DOIs
StatePublished - Sep 2006

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Heart Rate
Pharmaceutical Preparations
Potassium Channels
Sudden Cardiac Death
Syncope
Cardiac Arrhythmias
Analysis of Variance
Electrocardiography
Exercise
Safety
ibutilide

Keywords

  • Corrected QT interval
  • Drug development
  • QT interval
  • Torsades de pointes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Bazett and Fridericia QT correction formulas interfere with measurement of drug-induced changes in QT interval. / Indik, Julia H; Pearson, Ellen C.; Fried, Karen; Woosley, Raymond L.

In: Heart Rhythm, Vol. 3, No. 9, 09.2006, p. 1003-1007.

Research output: Contribution to journalArticle

Indik, Julia H ; Pearson, Ellen C. ; Fried, Karen ; Woosley, Raymond L. / Bazett and Fridericia QT correction formulas interfere with measurement of drug-induced changes in QT interval. In: Heart Rhythm. 2006 ; Vol. 3, No. 9. pp. 1003-1007.
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N2 - Background: The QT interval on the ECG is prolonged by more than 50 marketed drugs, an effect that has been associated with syncope and/or sudden cardiac death due to an arrhythmia. Because changes in heart rate also change the QT interval, it has become standard practice to use a correction formula, such as the Bazett formula, to normalize the QT interval to a heart rate of 60 bpm, that is, the rate-corrected QT or QTc. Numerous other formulas have been devised to make this correction, including the Fridericia, Hodges, and Framingham formulas. Objectives: The purpose of this study was to investigate how the Bazett formula and three other formulas influence assessment of the QT-prolonging effect of the potassium channel-blocking drug ibutilide. Methods: Using a standardized physical activity protocol, the QT interval was assessed over a broad range of heart rates before and after an infusion of ibutilide (4.75 μg/kg) that produced a stable 15- to 20-ms QT prolongation in consenting normal subjects (9 men and 9 women). The QT interval was measured digitally over a range of heart rates from 60 to 120 bpm, and then four correction formulas (Bazett, Fridericia, Framingham, or Hodges) were applied. The uncorrected change in QT interval due to ibutilide was compared with the change using each of the formulas by repeated measures analysis of variance. Results: At heart rates from 60 to 120 bpm, the Bazett and Fridericia correction formulas overestimated the change in QT in both men and women (P <.001). However, the Framingham and Hodges formulas did not alter the accuracy of the assessment of QT interval change. Conclusion: Rate correction of QT intervals using the standard Bazett and Fridericia formulas can introduce significant errors in the assessment of drug effects on the QT interval. This has implications for the clinical assessment of drug effects and for the safety assessment of new drugs under development.

AB - Background: The QT interval on the ECG is prolonged by more than 50 marketed drugs, an effect that has been associated with syncope and/or sudden cardiac death due to an arrhythmia. Because changes in heart rate also change the QT interval, it has become standard practice to use a correction formula, such as the Bazett formula, to normalize the QT interval to a heart rate of 60 bpm, that is, the rate-corrected QT or QTc. Numerous other formulas have been devised to make this correction, including the Fridericia, Hodges, and Framingham formulas. Objectives: The purpose of this study was to investigate how the Bazett formula and three other formulas influence assessment of the QT-prolonging effect of the potassium channel-blocking drug ibutilide. Methods: Using a standardized physical activity protocol, the QT interval was assessed over a broad range of heart rates before and after an infusion of ibutilide (4.75 μg/kg) that produced a stable 15- to 20-ms QT prolongation in consenting normal subjects (9 men and 9 women). The QT interval was measured digitally over a range of heart rates from 60 to 120 bpm, and then four correction formulas (Bazett, Fridericia, Framingham, or Hodges) were applied. The uncorrected change in QT interval due to ibutilide was compared with the change using each of the formulas by repeated measures analysis of variance. Results: At heart rates from 60 to 120 bpm, the Bazett and Fridericia correction formulas overestimated the change in QT in both men and women (P <.001). However, the Framingham and Hodges formulas did not alter the accuracy of the assessment of QT interval change. Conclusion: Rate correction of QT intervals using the standard Bazett and Fridericia formulas can introduce significant errors in the assessment of drug effects on the QT interval. This has implications for the clinical assessment of drug effects and for the safety assessment of new drugs under development.

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KW - Torsades de pointes

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