Variability of heart rate correction methods for the QT interval

Mehul Desai, Lang Li, Zeruesenay Desta, Marek Malik, David Flockhart

Research output: Contribution to journalArticle

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Abstract

Aims: To compare variability, of heart rate-corrected QT intervals (QTc) using three different methods in a study of low-dose oral haloperidol. Methods: In a randomized, double-blind, placebo-controlled, crossover trial, we studied QT interval pharmacodynamics of single doses of oral haloperidol (10 mg) in 16 healthy subjects. Heart rate correction of the QT interval was performed using Bazett's, Fridericia's and subject-specific correction methods. The subject-specific correction was performed using linear mixed modelling of placebo period QT vs RR data from each study subject. Results: The subject-specific correction, in the form of QTc = QT/RRα, yielded a correction term α (slope of the log-transformed QT vs RR relationship) that ranged from 0.23 to 0.38 in individual subjects, i.e. the fixed correction term α = 0.5 of Bazett's correction was outside and the fixed correction term α = 0.33 of Fridericia's correction inside the range of individual values. The mean absolute slope of the QTc vs RR regression line using the subject-specific correction was significantly lower than the mean slopes obtained using either Bazett's or Fridericia's corrections. All three methods revealed a statistically significant greater mean QTc on haloperidol than on placebo at 10 h post-drug administration. The mean QT (95% CI) was 421.6 (410.8, 432.4), and 408.4 (398.6, 417.8) on haliperidol and placebo, respectively, using the subject-specific correction method (P = 0.0053). The mean QTc (95% CI) was 425.4 (414.3, 436.5) and 403.1 (394.3, 411.9) on haliperidol and placebo, respectively, using Bazett's correction (P = 1.7 × 10-5) and 423.1 (412.6, 433.6) and 408.2 (398.6, 417.8) on haliperidol and placebo, respectively, using Fridericia's correction (P = 7.7 × 10-4). Raw P-values were calculated using a paired t-test. Bonferroni-corrected P-values were calculated by multiplying the raw P-values by 13. Conclusion Haloperidol caused a statistically significant mean QTc prolongation using the three correction methods. The QTc intervals were less dependent on RR intervals using the subject-specific method, thus decreasing the possibility of over- or under-correction. The interindividual QTc changes from baseline varied significantly depending on the method of correction used.

Original languageEnglish
Pages (from-to)511-517
Number of pages7
JournalBritish Journal of Clinical Pharmacology
Volume55
Issue number6
DOIs
StatePublished - Jun 1 2003

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Heart Rate
Placebos
Haloperidol
Cross-Over Studies
Healthy Volunteers
Pharmaceutical Preparations

Keywords

  • Haloperidol
  • Heart rate correction
  • QT interval

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Variability of heart rate correction methods for the QT interval. / Desai, Mehul; Li, Lang; Desta, Zeruesenay; Malik, Marek; Flockhart, David.

In: British Journal of Clinical Pharmacology, Vol. 55, No. 6, 01.06.2003, p. 511-517.

Research output: Contribution to journalArticle

Desai, Mehul ; Li, Lang ; Desta, Zeruesenay ; Malik, Marek ; Flockhart, David. / Variability of heart rate correction methods for the QT interval. In: British Journal of Clinical Pharmacology. 2003 ; Vol. 55, No. 6. pp. 511-517.
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abstract = "Aims: To compare variability, of heart rate-corrected QT intervals (QTc) using three different methods in a study of low-dose oral haloperidol. Methods: In a randomized, double-blind, placebo-controlled, crossover trial, we studied QT interval pharmacodynamics of single doses of oral haloperidol (10 mg) in 16 healthy subjects. Heart rate correction of the QT interval was performed using Bazett's, Fridericia's and subject-specific correction methods. The subject-specific correction was performed using linear mixed modelling of placebo period QT vs RR data from each study subject. Results: The subject-specific correction, in the form of QTc = QT/RRα, yielded a correction term α (slope of the log-transformed QT vs RR relationship) that ranged from 0.23 to 0.38 in individual subjects, i.e. the fixed correction term α = 0.5 of Bazett's correction was outside and the fixed correction term α = 0.33 of Fridericia's correction inside the range of individual values. The mean absolute slope of the QTc vs RR regression line using the subject-specific correction was significantly lower than the mean slopes obtained using either Bazett's or Fridericia's corrections. All three methods revealed a statistically significant greater mean QTc on haloperidol than on placebo at 10 h post-drug administration. The mean QT (95{\%} CI) was 421.6 (410.8, 432.4), and 408.4 (398.6, 417.8) on haliperidol and placebo, respectively, using the subject-specific correction method (P = 0.0053). The mean QTc (95{\%} CI) was 425.4 (414.3, 436.5) and 403.1 (394.3, 411.9) on haliperidol and placebo, respectively, using Bazett's correction (P = 1.7 × 10-5) and 423.1 (412.6, 433.6) and 408.2 (398.6, 417.8) on haliperidol and placebo, respectively, using Fridericia's correction (P = 7.7 × 10-4). Raw P-values were calculated using a paired t-test. Bonferroni-corrected P-values were calculated by multiplying the raw P-values by 13. Conclusion Haloperidol caused a statistically significant mean QTc prolongation using the three correction methods. The QTc intervals were less dependent on RR intervals using the subject-specific method, thus decreasing the possibility of over- or under-correction. The interindividual QTc changes from baseline varied significantly depending on the method of correction used.",
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AU - Desai, Mehul

AU - Li, Lang

AU - Desta, Zeruesenay

AU - Malik, Marek

AU - Flockhart, David

PY - 2003/6/1

Y1 - 2003/6/1

N2 - Aims: To compare variability, of heart rate-corrected QT intervals (QTc) using three different methods in a study of low-dose oral haloperidol. Methods: In a randomized, double-blind, placebo-controlled, crossover trial, we studied QT interval pharmacodynamics of single doses of oral haloperidol (10 mg) in 16 healthy subjects. Heart rate correction of the QT interval was performed using Bazett's, Fridericia's and subject-specific correction methods. The subject-specific correction was performed using linear mixed modelling of placebo period QT vs RR data from each study subject. Results: The subject-specific correction, in the form of QTc = QT/RRα, yielded a correction term α (slope of the log-transformed QT vs RR relationship) that ranged from 0.23 to 0.38 in individual subjects, i.e. the fixed correction term α = 0.5 of Bazett's correction was outside and the fixed correction term α = 0.33 of Fridericia's correction inside the range of individual values. The mean absolute slope of the QTc vs RR regression line using the subject-specific correction was significantly lower than the mean slopes obtained using either Bazett's or Fridericia's corrections. All three methods revealed a statistically significant greater mean QTc on haloperidol than on placebo at 10 h post-drug administration. The mean QT (95% CI) was 421.6 (410.8, 432.4), and 408.4 (398.6, 417.8) on haliperidol and placebo, respectively, using the subject-specific correction method (P = 0.0053). The mean QTc (95% CI) was 425.4 (414.3, 436.5) and 403.1 (394.3, 411.9) on haliperidol and placebo, respectively, using Bazett's correction (P = 1.7 × 10-5) and 423.1 (412.6, 433.6) and 408.2 (398.6, 417.8) on haliperidol and placebo, respectively, using Fridericia's correction (P = 7.7 × 10-4). Raw P-values were calculated using a paired t-test. Bonferroni-corrected P-values were calculated by multiplying the raw P-values by 13. Conclusion Haloperidol caused a statistically significant mean QTc prolongation using the three correction methods. The QTc intervals were less dependent on RR intervals using the subject-specific method, thus decreasing the possibility of over- or under-correction. The interindividual QTc changes from baseline varied significantly depending on the method of correction used.

AB - Aims: To compare variability, of heart rate-corrected QT intervals (QTc) using three different methods in a study of low-dose oral haloperidol. Methods: In a randomized, double-blind, placebo-controlled, crossover trial, we studied QT interval pharmacodynamics of single doses of oral haloperidol (10 mg) in 16 healthy subjects. Heart rate correction of the QT interval was performed using Bazett's, Fridericia's and subject-specific correction methods. The subject-specific correction was performed using linear mixed modelling of placebo period QT vs RR data from each study subject. Results: The subject-specific correction, in the form of QTc = QT/RRα, yielded a correction term α (slope of the log-transformed QT vs RR relationship) that ranged from 0.23 to 0.38 in individual subjects, i.e. the fixed correction term α = 0.5 of Bazett's correction was outside and the fixed correction term α = 0.33 of Fridericia's correction inside the range of individual values. The mean absolute slope of the QTc vs RR regression line using the subject-specific correction was significantly lower than the mean slopes obtained using either Bazett's or Fridericia's corrections. All three methods revealed a statistically significant greater mean QTc on haloperidol than on placebo at 10 h post-drug administration. The mean QT (95% CI) was 421.6 (410.8, 432.4), and 408.4 (398.6, 417.8) on haliperidol and placebo, respectively, using the subject-specific correction method (P = 0.0053). The mean QTc (95% CI) was 425.4 (414.3, 436.5) and 403.1 (394.3, 411.9) on haliperidol and placebo, respectively, using Bazett's correction (P = 1.7 × 10-5) and 423.1 (412.6, 433.6) and 408.2 (398.6, 417.8) on haliperidol and placebo, respectively, using Fridericia's correction (P = 7.7 × 10-4). Raw P-values were calculated using a paired t-test. Bonferroni-corrected P-values were calculated by multiplying the raw P-values by 13. Conclusion Haloperidol caused a statistically significant mean QTc prolongation using the three correction methods. The QTc intervals were less dependent on RR intervals using the subject-specific method, thus decreasing the possibility of over- or under-correction. The interindividual QTc changes from baseline varied significantly depending on the method of correction used.

KW - Haloperidol

KW - Heart rate correction

KW - QT interval

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