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Implications of Individual QT/RR Profiles-Part 2: Zero QTc/RR Correlations Do Not Prove QTc Correction Accuracy in Studies of QTc Changes.

ABSTRACT: INTRODUCTION: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). OBJECTIVE: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. METHODS: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. RESULTS: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. CONCLUSIONS: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.

SUBMITTER: Malik M

PROVIDER: S-EPMC6426831 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Implications of Individual QT/RR Profiles-Part 2: Zero QTc/RR Correlations Do Not Prove QTc Correction Accuracy in Studies of QTc Changes.

Malik Marek M Garnett Christine C Hnatkova Katerina K Vicente Jose J Johannesen Lars L Stockbridge Norman N

Drug safety 20190301 3

<h4>Introduction</h4>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).<h4>Objecti ...[more]

PMID: 30255348

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Project description:INTRODUCTION:Universal QT correction formulas are potentially problematic in corrected QT (QTc) interval comparisons at different heart rates. Instead of individual-specific corrections, population-specific corrections are occasionally used based on QT/RR data pooled from all study subjects. OBJECTIVE:To investigate the performance of individual-specific and population-specific corrections, a statistical modeling study was performed using QT/RR data of 523 healthy subjects. METHODS:In each subject, full drug-free QT/RR profiles were available, characterized using non-linear regression models. In each subject, 50 baseline QT/RR readings represented baseline data of standard QT studies. Using these data, linear and log-linear heart rate corrections were optimized for each subject and for different groups of ten and 50 subjects. These corrections were applied in random combinations of heart rate changes between - 10 and + 25 beats per minute (bpm) and known QTc interval changes between - 25 and + 25 ms. RESULTS:Both the subject-specific and population-specific corrections based on the 50 baseline QT/RR readings tended to underestimate/overestimate the QTc interval changes when heart rate was increasing/decreasing, respectively. The result spread was much wider with population-specific corrections, making the estimates of QTc interval changes practically unpredictable. CONCLUSION:Subject-specific heart rate corrections based on limited baseline drug-free data may lead to inconsistent results and, in the presence of underlying heart rate changes, may potentially underestimate or overestimate QTc interval changes. The population-specific corrections lead to results that are much more influenced by the combination of individual QT/RR patterns than by the actual QTc interval changes. Subject-specific heart rate corrections based on full profiles derived from drug-free baseline recordings with wide QT/RR distribution should be used when studying drugs expected to cause heart rate changes.

Dataset Information

Implications of Individual QT/RR Profiles-Part 2: Zero QTc/RR Correlations Do Not Prove QTc Correction Accuracy in Studies of QTc Changes.

Publications

Implications of Individual QT/RR Profiles-Part 2: Zero QTc/RR Correlations Do Not Prove QTc Correction Accuracy in Studies of QTc Changes.

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