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/RRalpha, yielded a correction term alpha (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 alpha = 0.5 of Bazett's correction was outside and the fixed correction term alpha = 0.33 of Fridericia's correction inside the range of individual values. The mean absolute slope of the QTcvs 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 x 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 x 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.