12-lead resting ECGs are considered essential in clinical trials, but their limitations have led to increasing use of 12-lead Holter monitor devices. There is, however, a lack of data comparing the two approaches. Using our expertise in clinical trial methodologies, Richmond Research Institute, a world-class clinical research facility in London, can now provide this important insight.
To understand the physiological effects of new drugs, 12-lead resting electrocardiograms (ECGs) are considered essential to record the heart's rhythm, rate, and electrical activity. These recordings provide important information on cardiac safety by allowing the time it takes for the heart's ventricles to contract and relax, called the QT interval, to be measured.
The logistical aspect of performing ECGs during clinical trials means limited numbers can be recorded, resulting in long periods between assessment time points. Valuable safety information may, therefore, be missed when cardiac activity is not being monitored. These limitations have led to the increased use of 12lead Holter monitors, portable ECG devices that provides continuous data recordings while reducing patient and staff burden. However, there is a lack of data comparing the quality and effectiveness of QT interval recordings obtained from multiple ECGs versus continuous Holter monitor output.
In this trial, we compared the effectiveness of multiple ECGs versus continuous Holter monitoring in accurately determining QT intervals and other ECG parameter changes. We also compared two different Holter algorithms (GE Getemed and BRAVO) to uncover any discrepancies in the automated measurement of QTcF¹ and heart rate between the two algorithms.
Healthy Caucasian and Japanese men and women (between 21 and 45 years of age) took part in a randomised, placebo-controlled clinical trial to investigate the effect of an intravenous drug on the QT/QTc interval. The data analysed in our study were obtained pre-dose from 35 volunteers during this thorough QT/QTc clinical trial.
Data were obtained from volunteers on Day −1 via continuous 12-lead Holter monitor recordings. Resting 12lead ECGs were performed at specific time points (at dosing, and again at 2, 8, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, and 12 hours pre-dosing).
Individual heart rate and QTcF data were calculated by both algorithms at 10-minute intervals alongside average (mean) data values. We also compared differences in average heart rate and QTcF measurements when both resting ECG and Holter monitor data were analysed using the BRAVO algorithm to identify differences between the recording devices.
A thorough analysis showed minimal, non-significant differences between resting ECG and Holter monitor measurements for heart rate, QTcF, and other parameters. However, the degree of concordance could not be determined after the 6-hour time point because resting ECGs were not performed again until 12 hours post-dose.
For the Holter algorithm comparison, GE Getemed provided values approximately 10 milliseconds (ms) greater than those calculated using the BRAVO algorithm. This variation was consistent across all timepoints. Little difference was seen in the measurement of heart rate by the two algorithms.
Using a 12-lead Holter monitor to provide continuous feedback about changes in heart rate, QTcF, and other ECG parameters would appear to be a preferable and more convenient approach to obtain safety data at fixed timepoints from standard resting ECGs. However, we found a small but consistent disparity of approximately 10 ms between the GE Getemed and BRAVO algorithms concerning Holter measurements of the QTcF interval.
It is important to note that even a small difference in QTcF interval measurement could have significant implications on patient safety and the validity of clinical trial data because conflicting conclusions may be drawn depending on the algorithm used. This difference may be even more pronounced among volunteers receiving investigational drugs.
Our study concluded that performing resting ECGs at pre-defined post-dose timepoints could prove useful in complementing Holter monitor measurements and help to verify post-dose changes and concentration effects observed in clinical trials of new drugs.
Read the full results in the paper published in Annals of Noninvasive Electrocardiology.
Authored by Georg Ferber, PhD, Dilshat Djumanov, PhD, Ulrike Lorch, MD, FFPM, Edward Jackson, BSc, MSc, PhD, MBChB, Joao Almeida Melo, James Rickard, MPharm, and Jorg Taubel, MD, FFPM, FESC.
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