National Heart and Lung Institute, Imperial College, Dovehouse Street, London, SW3 6LY, England, UK.
Division of Cardiovascular and Renal Products, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
Drug Saf. 2019 Mar;42(3):415-426. doi: 10.1007/s40264-018-0735-2.
In studies of drug-induced corrected QT (QTc) changes, fixed universal heart rate (HR) corrections (e.g., the Fridericia correction) are potentially misleading when assessing the effects of drugs that change HR. When data-specific corrections are designed, tests of their validity are needed. The proposed tests include zero correlations between QTc and corresponding RR values in the complete study data (pooling on-treatment and off-treatment interval measurements).
To document that this approach is potentially highly misleading, a statistical modeling study was conducted based on the full profiles of QT/RR data of 523 healthy subjects-254 females, mean age 33.5 years.
In each of the subjects, 50 baseline QT/RR readings were selected to model baseline data. In repeated experiments, groups of ten and 50 subjects were randomly selected and drug-induced HR increases between 0 and 25 beats per minute combined with QTc changes between - 20 and + 20 ms were modeled. In each experiment, subject-specific as well as population-specific HR corrections were designed so that the QTc interval data were uncorrelated to the corresponding RR interval data.
The simulation experiments showed that when zero correlations of QTc data with RR data are combined with more than trivial HR increases, the HR corrections are substantially biased and underestimate or fully eliminate any drug-induced QTc interval changes. This result is in full agreement with theoretical considerations of HR correction principles.
The lack of correlation of QTc versus RR durations including on-treatment data does not prove any validity of HR corrections. Correlations of QTc versus RR in study data pooling on- and off-drug measurements should not be used to prove the appropriateness of HR corrections.
在药物引起的校正 QT（QTc）变化的研究中，当评估改变心率的药物的影响时，固定的通用心率（HR）校正（例如 Fridericia 校正）可能会产生误导。当设计数据特定的校正时，需要对其有效性进行检验。提出的检验包括在完整的研究数据中（合并治疗和治疗间隔测量值），QTc 与相应 RR 值之间的零相关性。
为了证明这种方法可能存在高度误导性，我们基于 523 名健康受试者的 QT/RR 数据的完整概况进行了一项统计建模研究，其中包括 254 名女性，平均年龄 33.5 岁。
在每个受试者中，选择 50 个基线 QT/RR 读数来对基线数据进行建模。在重复的实验中，随机选择 10 名和 50 名受试者组成的群组，并对心率增加 0 至 25 次/分钟与 QTc 变化 -20 至 +20 毫秒相结合的情况进行建模。在每个实验中，设计了个体特异性和群体特异性 HR 校正，使 QTc 间隔数据与相应的 RR 间隔数据没有相关性。
模拟实验表明，当 QTc 数据与 RR 数据的零相关性与超过微小的 HR 增加相结合时，HR 校正会产生实质性的偏差，并低估或完全消除任何药物引起的 QTc 间隔变化。这一结果与 HR 校正原理的理论考虑完全一致。
QTc 与 RR 持续时间（包括治疗期间的数据）缺乏相关性并不能证明 HR 校正的有效性。在研究数据中，将治疗期间和治疗期间的数据进行混合，以 QTc 与 RR 的相关性来证明 HR 校正的适当性是不可取的。
