Individual QT-R-R relationship: Average stability over time does not rule out an individual residual variability: Implication for the assessment of drug effect on the QT interval

Background: Universal QT correction formulae have been shown to under or overcorrect the QT interval duration. Individual QT-R-R modeling has been proposed as a preferable solution for heart rate correction of QT intervals. However, the QT-R-R relationship stability over time needs to be evaluated. Methods: The present report is part of randomized, double-dummy, and placebo-controlled 4-way crossover phase 1 study (48 healthy volunteers). Each randomized period included a run-in placebo day followed the day after by drug administration, with moxifloxacin as a positive control for QT interval measurement. Digital Holter ECG data were analyzed using the "bin" approach. For each period, individual QT-R-R relationship were calculated using two different models (linear and parabolic log-log models). Results: The mean intrasubject variability for the alpha coefficient of the linear modeling (SDintra 0.011 +/- 0.005) reached 28.6 +/- 10.2%. When the parabolic model was considered, the SDintra was 0.026 +/- 0.009 for the alpha coefficient. The QT-R-R relationship variability was in part related to long-term RR changes (R-2 = 30%, P < 0.05). However, no significant time effect (ANOVA) was evidenced for QT-R-R coefficients. Moxifloxacin significantly increased the a coefficient of the QT- R-R relationship from 0.07 +/- 0.018 to 0.085 +/- 0.019, P < 0.05 (linear model). Conclusions: The individual QT-R-R relationship shows a residual variability in part related to long-term autonomic changes. In addition, the QT-R-R relationship might be modulated by the drug tested. As a consequence, pretherapy QT-R-R relationship obtained in a given patient cannot be used as a fingerprint throughout a drug trial.