Hnatkova Katerina, Vicente Jose, Johannesen Lars, Garnett Christine, Stockbridge Norman, Malik Marek
National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Division of Cardiovascular and Renal Products, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, United States.
Front Physiol. 2019 Jun 18;10:635. doi: 10.3389/fphys.2019.00635. eCollection 2019.
The accuracy of studies of drug-induced QTc changes depends, among others, on the accuracy of heart rate correction of QT interval. It has been recognized that when a drug leads to substantial heart rate changes, fixed universal corrections cannot be used and that alternative methods such as subject-specific corrections established for each study participant need to be considered. Nevertheless, the maximum heart rate change that permits use of fixed correction with reasonable accuracy has not been systematically investigated. We have therefore used full QT/heart-rate profiles of 751 healthy subjects (mean age 34.2 ± 9.6, range 18-61 years, 335 females) and compared their subject-specific corrections with 6 fixed corrections, namely Bazett, Fridericia, Framingham, Hodges, Rautaharju, and Sarma formulae. The comparison was based on statistical modeling experiments which simulated clinical studies of = 10 or = 50 female or male subjects. The experiments compared errors of ΔQTc intervals calculated as differences between QTc intervals at an initial heart rate (in the range of 40 to 120 beats per minute, bpm) and after a heart rate change (in the range from -20 to +20 bpm). The experiments also investigated errors due to spontaneous heart rate fluctuation and due to omission of correction for QT/RR hysteresis. In each experiment, the absolute value of the single-sided 90th percentile most remote from zero was used as the error estimate. Each experiment was repeated 10,000 times with random selection of modeled study group. From these repetitions, median and upper 80th percentile was derived and graphically displayed for all different combinations of initial heart rate and heart rate change. The results showed that Fridericia formula might be reasonable (with estimated errors of ΔQTc below 8 ms) in large studies if the heart rate does not change more than ± 10 bpm and that the errors by fixed corrections and the errors due to omission of QR/RR hysteresis are additive. Additionally, the results suggest that the variability introduced into QTc data by not correcting for the underlying heart rate accurately might have a greater impact in smaller studies. The errors by Framingham formula were practically the same as with the Fridericia formula. Other investigated fixed heart rate corrections led to larger ΔQTc errors.
药物诱导的QTc变化研究的准确性，尤其取决于QT间期心率校正的准确性。人们已经认识到，当一种药物导致心率大幅变化时，不能使用固定通用的校正方法，而需要考虑诸如为每个研究参与者建立的个体特异性校正等替代方法。然而，允许以合理准确性使用固定校正的最大心率变化尚未得到系统研究。因此，我们使用了751名健康受试者（平均年龄34.2±9.6岁，范围18 - 61岁，335名女性）的完整QT/心率曲线，并将他们的个体特异性校正与6种固定校正方法进行了比较，即巴泽特（Bazett）、弗里德里西亚（Fridericia）、弗雷明汉姆（Framingham）、霍奇斯（Hodges）、劳塔哈尔尤（Rautaharju）和萨尔马（Sarma）公式。该比较基于统计建模实验，这些实验模拟了10名或50名女性或男性受试者的临床研究。实验比较了ΔQTc间期的误差，该误差计算为初始心率（在每分钟40至120次心跳，bpm范围内）和心率变化后（在-20至+20 bpm范围内）QTc间期之间的差异。实验还研究了由于自发心率波动以及由于遗漏QT/RR滞后校正而导致的误差。在每个实验中，将最远离零的单侧第90百分位数的绝对值用作误差估计。每个实验随机选择模拟研究组重复进行10000次。从这些重复实验中，得出中位数和第80百分位数上限，并以图形方式显示初始心率和心率变化的所有不同组合。结果表明，如果心率变化不超过±10 bpm，弗里德里西亚公式在大型研究中可能是合理的（ΔQTc估计误差低于8毫秒），并且固定校正的误差和由于遗漏QR/RR滞后导致的误差是相加的。此外，结果表明，在较小的研究中，未准确校正基础心率而引入到QTc数据中的变异性可能具有更大的影响。弗雷明汉姆公式的误差与弗里德里西亚公式的误差实际上相同。其他研究的固定心率校正导致更大的ΔQTc误差。
