Control of rapid heart rate changes for electrocardiographic analysis: implications for thorough QT studies

Abstract

Background: Following an abrupt change in heart rate (HR), QT adaptation is achieved within a delayed time frame.

Hypothesis: The exclusion of electrocardiograms (ECGs) showing rapid HR changes influences the level of a drug-induced QT prolongation.

Methods: Continuous 12-lead ECG-Holter monitoring was performed in 31 healthy subjects. Using the "bin" method, we evaluated moxifloxacin effects on (1) QT interval duration at different RR intervals and (2) on the rate dependence of QT interval. These endpoints were calculated separately for five types of ECG analysis: classification of cardiac complexes based on (a) the single preceding RR interval (RR-1) and (b) RR filters excluding rapid HR changes according to the formula RR-1 = RR[time-window] +/- threshold, where the time-window could be 30 or 60 s (R30 and R60) and the threshold 15 or 30 ms (th15 or th30).

Results: Moxifloxacin-induced QT prolongation was consistently higher using the stable models when compared with the RR-1 model. Moxifloxacin-induced QT prolongation at RR = 1000 ms was 8.2 +/- 11.2 vs. 10.9 +/- 10.4 ms using the RR-1 and R60th15 stable models, respectively (p < 0.05). Moxifloxacin-induced QT prolongation was more pronounced at slow than at fast HR. This so-called "reverse rate-dependent" effect was more pronounced when assessed using stable HR models (0.023 IC95% [0.019;0.027] vs. 0.015 IC95% [0.012;0.017] using the RR-1 model).

Conclusion: The exclusion of ECGs with rapid HR changes influences the magnitude of drug-induced QT changes. The hysteresis phenomenon should not be neglected when dedicated QT studies are performed.