Importance of QT/RR hysteresis correction in studies of drug-induced QTc interval changes

QT/RR hysteresis and QT/RR adaptation are interlinked but separate physiological processes signifying how quickly and how much QT interval changes when heart rate changes, respectively. While QT interval duration is, as a rule, corrected for heart rate in terms of the QT/RR adaptation, the correction for QT/RR hysteresis is frequently omitted in studies of drug-induced QTc changes. This study used data from previously conducted thorough QT studies to investigate the extent of QTc errors caused by omitting the correction for QT/RR hysteresis, particularly in small clinical investigations. Statistical modeling approach was used to generate 11,000 simulated samples of 10-subject studies in which mixed effect PK/PD models were used to estimate drug-induced QTc changes at mean maximum plasma concentration of investigated compounds. Calculations of QTc intervals involving and omitting QT/RR hysteresis correction were compared. These comparisons showed that ignoring QT/RR hysteresis has two undesirable effects: (A) In the design of subject-specific heart rate corrections (needed in studies of drugs that change heart rate) omission of QT/RR hysteresis may lead to signals of QTc prolongation of more than 10 ms to be missed. (B) Irrespective of whether the investigated drug changes heart rate, omission of QT/RR hysteresis causes the widths of the confidence intervals of the PK/PD predicted QTc interval changes to be increased by 20-30% on average (exceeding 50% in some cases). This may lead to a failure of excluding meaningful QTc prolongation which would be excluded if using hysteresis correction. The study concludes that correction for QT/RR hysteresis should be incorporated into future studies of drug-induced QTc changes. Subject-specific heart rate corrections that omit hysteresis correction may lead to erroneously biased conclusions. Even when using universal (e.g. Fridericia) heart rate correction, hysteresis correction decreases the confidence intervals of QTc changes and thus helps avoiding false positive outcomes.