Errors of Fixed QT Heart Rate Corrections Used in the Assessment of Drug-Induced QTc Changes
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...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2019-06-01
|
| Series: | Frontiers in Physiology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fphys.2019.00635/full |
| _version_ | 1818487881650405376 |
|---|---|
| author | Katerina Hnatkova Jose Vicente Lars Johannesen Christine Garnett Norman Stockbridge Marek Malik |
| author_facet | Katerina Hnatkova Jose Vicente Lars Johannesen Christine Garnett Norman Stockbridge Marek Malik |
| author_sort | Katerina Hnatkova |
| collection | DOAJ |
| description | 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 N = 10 or N = 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. |
| first_indexed | 2024-12-10T16:44:03Z |
| format | Article |
| id | doaj.art-25a5d8d4e3804103a71d2b5f3e849551 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-10T16:44:03Z |
| publishDate | 2019-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-25a5d8d4e3804103a71d2b5f3e8495512022-12-22T01:41:06ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2019-06-011010.3389/fphys.2019.00635461617Errors of Fixed QT Heart Rate Corrections Used in the Assessment of Drug-Induced QTc ChangesKaterina Hnatkova0Jose Vicente1Lars Johannesen2Christine Garnett3Norman Stockbridge4Marek Malik5National Heart and Lung Institute, Imperial College London, London, United KingdomDivision 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 StatesDivision 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 StatesDivision 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 StatesDivision 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 StatesNational Heart and Lung Institute, Imperial College London, London, United KingdomThe 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 N = 10 or N = 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.https://www.frontiersin.org/article/10.3389/fphys.2019.00635/fulldrug safetydrug-induced QTc changesheart rate correction of QT intervalFridericia QTc formulaFramingham QTc formulasubject-specific QTc corrections |
| spellingShingle | Katerina Hnatkova Jose Vicente Lars Johannesen Christine Garnett Norman Stockbridge Marek Malik Errors of Fixed QT Heart Rate Corrections Used in the Assessment of Drug-Induced QTc Changes Frontiers in Physiology drug safety drug-induced QTc changes heart rate correction of QT interval Fridericia QTc formula Framingham QTc formula subject-specific QTc corrections |
| title | Errors of Fixed QT Heart Rate Corrections Used in the Assessment of Drug-Induced QTc Changes |
| title_full | Errors of Fixed QT Heart Rate Corrections Used in the Assessment of Drug-Induced QTc Changes |
| title_fullStr | Errors of Fixed QT Heart Rate Corrections Used in the Assessment of Drug-Induced QTc Changes |
| title_full_unstemmed | Errors of Fixed QT Heart Rate Corrections Used in the Assessment of Drug-Induced QTc Changes |
| title_short | Errors of Fixed QT Heart Rate Corrections Used in the Assessment of Drug-Induced QTc Changes |
| title_sort | errors of fixed qt heart rate corrections used in the assessment of drug induced qtc changes |
| topic | drug safety drug-induced QTc changes heart rate correction of QT interval Fridericia QTc formula Framingham QTc formula subject-specific QTc corrections |
| url | https://www.frontiersin.org/article/10.3389/fphys.2019.00635/full |
| work_keys_str_mv | AT katerinahnatkova errorsoffixedqtheartratecorrectionsusedintheassessmentofdruginducedqtcchanges AT josevicente errorsoffixedqtheartratecorrectionsusedintheassessmentofdruginducedqtcchanges AT larsjohannesen errorsoffixedqtheartratecorrectionsusedintheassessmentofdruginducedqtcchanges AT christinegarnett errorsoffixedqtheartratecorrectionsusedintheassessmentofdruginducedqtcchanges AT normanstockbridge errorsoffixedqtheartratecorrectionsusedintheassessmentofdruginducedqtcchanges AT marekmalik errorsoffixedqtheartratecorrectionsusedintheassessmentofdruginducedqtcchanges |