Clinical assessment of drug-induced QT prolongation in association with heart rate changes

Background: The formulas for heart rate (HR) correction of QT interval have been shown to overcorrect or undercorrect this interval with changes in HR. A Holter-monitoring method avoiding the need for any correction formulas is proposed as a means to assess drug-induced QT interval changes. Methods: A thorough QT study included 2 single doses of the alpha(1)-adrenergic receptor blocker alfuzosin, placebo, and a QT-positive control arm (moxifloxacin) in 48 healthy subjects. Bazett, Fridericia, population-specific (QTcN), and subject-specific (QTcNi) correction formulas were applied to 12-lead electrocardiographic recording data. QT(1000) (QT at RR = 1000 ins), QT largest bin (at the largest sample size bin), and QT average (average QT of all RR bins) were obtained from Holter recordings by use of custom software to perform rate-independent QT analysis. Results. The 3 Holter end points provided similar results, as follows: Moxifloxacin-induced QT prolongation was 7.0 ins (95% confidence interval [0], 4.4-9.6 ms) for QT(1000), 6.9 ms (95% CI, 4.8-9.1 ms) for QT largest bin, and 6.6 ins (95% CI, 4.6-8.6 ms) for QT average. At the therapeutic dose (10 mg), alfuzosin did not induce significant change in the QT. The 40-mg dose of alfuzosin increased HR by 3.7 beats/min and induced a small QT(1000) increase of 2.9 ms (95% CI, 0.3-5.5 ms) (QTcN, +4.6 ms [95% CI, 2.1-7.0 ms]; QTcNi, +4.7 ins [95% CI, 2.2-7.1 ms]). Data corrected by "universal" correction formulas still showed rate dependency and yielded larger QTc change estimations. The Holter method was able to show the drug-induced changes in QT rate dependence. Conclusions. The direct Holter-based QT interval measurement method provides an alternative approach to measure rate-independent estimates of QT interval changes during treatment.