Marek Malik1, Lars Johannesen2,3, Katerina Hnatkova4, Norman Stockbridge5. 1. National Heart and Lung Institute, Imperial College, Dovehouse Street, London, SW3 6LY, United Kingdom, UK. marek.malik@btinternet.com. 2. Division of Biomedical Physics, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, MD, USA. 3. Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden. 4. National Heart and Lung Institute, Imperial College, Dovehouse Street, London, SW3 6LY, United Kingdom, UK. 5. Division of Cardiovascular and Renal Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
Abstract
INTRODUCTION: Clinical pharmacology QT/QTc studies can be smaller if they more efficiently use the data generated. OBJECTIVE: The aim was to use large sets of electrocardiograms (ECGs) deposited at the US Food and Drug Administration to investigate the implications of heart rate measurement on the accuracy of QTc data. METHODS: Using the data of 80 thorough QT studies, we investigated whether placing study subjects in supine positions during short-term time points stabilizes heart rate (part I, based on 73 studies with 747,912 measured ECGs in 6786 healthy subjects) and whether heart rate measurements different from RR intervals captured simultaneously with QT intervals decrease QTc variability (part II, based on seven studies with 897,570 ECG measurements in 751 healthy subjects). RESULTS: In the part I data, when subjects were placed in supine undisturbed positions, heart rate instability (max-min of repeatedly measured heart rates within the same study time point) exceeding 5 beats per minute (bpm) was observed 40 % of the time and exceeded 10 bpm 10 % of the time. In the part II data, even when including QT measurements preceded by variable heart rates, correction of QT durations for RR interval values derived through a simple QT/RR hysteresis model with 95 % adaptation in 120 s led to mean intra-subject standard deviation of QTc (Fridericia formula) of only 7.14 ± 1.98 and 6.38 ± 1.50 ms in women and men, respectively. CONCLUSION: The QT/RR hysteresis model with 95 % adaptation in 120 s is universally applicable to healthy subjects, providing small QTc variability. Supine positions do not generally stabilize heart rates in healthy subjects. Universally applicable QT/RR hysteresis correction allows clinical QT/QTc studies to include variable heart rate episodes in the time points.
INTRODUCTION: Clinical pharmacology QT/QTc studies can be smaller if they more efficiently use the data generated. OBJECTIVE: The aim was to use large sets of electrocardiograms (ECGs) deposited at the US Food and Drug Administration to investigate the implications of heart rate measurement on the accuracy of QTc data. METHODS: Using the data of 80 thorough QT studies, we investigated whether placing study subjects in supine positions during short-term time points stabilizes heart rate (part I, based on 73 studies with 747,912 measured ECGs in 6786 healthy subjects) and whether heart rate measurements different from RR intervals captured simultaneously with QT intervals decrease QTc variability (part II, based on seven studies with 897,570 ECG measurements in 751 healthy subjects). RESULTS: In the part I data, when subjects were placed in supine undisturbed positions, heart rate instability (max-min of repeatedly measured heart rates within the same study time point) exceeding 5 beats per minute (bpm) was observed 40 % of the time and exceeded 10 bpm 10 % of the time. In the part II data, even when including QT measurements preceded by variable heart rates, correction of QT durations for RR interval values derived through a simple QT/RR hysteresis model with 95 % adaptation in 120 s led to mean intra-subject standard deviation of QTc (Fridericia formula) of only 7.14 ± 1.98 and 6.38 ± 1.50 ms in women and men, respectively. CONCLUSION: The QT/RR hysteresis model with 95 % adaptation in 120 s is universally applicable to healthy subjects, providing small QTc variability. Supine positions do not generally stabilize heart rates in healthy subjects. Universally applicable QT/RR hysteresis correction allows clinical QT/QTc studies to include variable heart rate episodes in the time points.
Authors: Velislav N Batchvarov; Azad Ghuran; Peter Smetana; Katerina Hnatkova; Monica Harries; Polychronis Dilaveris; A John Camm; Marek Malik Journal: Am J Physiol Heart Circ Physiol Date: 2002-06 Impact factor: 4.733
Authors: Marek Malik; Katerina Hnatkova; Donna Kowalski; James J Keirns; E Marcel van Gelderen Journal: Am J Physiol Heart Circ Physiol Date: 2013-10-25 Impact factor: 4.733
Authors: Katerina Hnatkova; Jose Vicente; Lars Johannesen; Christine Garnett; David G Strauss; Norman Stockbridge; Marek Malik Journal: Front Physiol Date: 2019-07-25 Impact factor: 4.566
Authors: Irena Andršová; Katerina Hnatkova; Martina Šišáková; Ondřej Toman; Peter Smetana; Katharina M Huster; Petra Barthel; Tomáš Novotný; Georg Schmidt; Marek Malik Journal: Sci Rep Date: 2021-07-12 Impact factor: 4.996
Authors: Robert B Kleiman; Borje Darpo; Michael Thorn; Thomas Stoehr; Frank Schippers Journal: Br J Clin Pharmacol Date: 2020-03-23 Impact factor: 4.335
Authors: Marek Malik; Christine Garnett; Katerina Hnatkova; Jose Vicente; Lars Johannesen; Norman Stockbridge Journal: Drug Saf Date: 2019-03 Impact factor: 5.606
Authors: Marek Malik; Christine Garnett; Katerina Hnatkova; Jose Vicente; Lars Johannesen; Norman Stockbridge Journal: Drug Saf Date: 2019-03 Impact factor: 5.228