Implications of methodological differences in digital electrocardiogram interval measurement

Abstract

Well-specified recommendations have yet to be established on how electrocardiogram (ECG) interval measurement should be performed by digital on-screen caliper systems to assess drug-induced effect on cardiac repolarization in pharmaceutical clinical trials with adequate precision and reproducibility. Since 1997, the industry has followed the European Committee for Proprietary Medicinal Products Points to Consider by using fully manual measurement of 3 consecutive sinus rhythm PQRST complexes in 1 lead only (typically limb lead II). More recently, semiautomatic measurement performed on representative (median) beats and based on the global leads has been considered. The International Conference on Harmonization E14 guidance (June 2005) advocates development of quality standards for centralized ECG interval measurement and allows all methods “whether or not assisted by computer” but includes no recommendations on how to perform the measurement. We provide an overview of the currently available methods for digital ECG interval measurement and the implications of between-method differences on quality of ECG interval measurements. We applied 4 methods most commonly used to assess QT prolongation (applied on 3 raw beats in limb lead II or by global measurement on 1 or 12 superimposed representative beats). QT, QTc Fridericia, and RR interval durations were measured on resting 12-lead digital ECGs obtained in 26 healthy volunteers predose and at 1, 2, and 3 hours after dosing with a single 160 mg oral dose of sotalol. Absolute interval durations and changes from baseline were compared between the 4 measurement methods. A better understanding of the implications from different measurement methodologies will facilitate more informed choice of the appropriate method for ECG interval measurement on clinical trials.

Introduction

The Food and Drug Administration's Digital ECG Initiative from 2001 mandates that, for new drug approvals, digital electrocardiograms must be submitted from definitive (“thorough”) QT studies and that the interval measurements be performed with annotations detailing exact offset and onset points on the ECG.¹ In consequence, digital ECG tracings and on-screen calipers have replaced paper ECG printouts and digitizing board as the primary tools for ECG acquisition and interval measurement in intensive QT assessment in clinical trials.2, 3 The new digital ECG environment has multiple important advantages over paper ECG for the investigating site, the core ECG laboratory, the sponsor, and the regulatory agencies, offering improvements of transmission, management, measurement, storage, and review of ECG data. Very important among these advantages is a completely new and improved approach to measure the intervals and evaluate waveform morphology on digital ECG. The only written recommendations for ECG interval measurement widely accepted before the digital era were published in 1997 by the European Committee for Proprietary Medicinal Products (CPMP) and were based on annotating 3 consecutive sinus complex, preferably from lead II.⁴ At that time, detection of drug effects on cardiac repolarization was mostly exclusively based on paper ECG and was associated with considerable degree of variability and measurement errors.⁵ Usage of manual digitizing board measurement methods was capable to detect measurement variations in the range of milliseconds6, 7; yet, the precision of the measurements was still relatively poor.⁸

The introduction of on-screen methodologies based on digital ECGs has completely changed the measuring environment. For example, the potential advantages of implementing digital algorithms are now being considered.⁹ Consequently, pharmaceutical sponsors nowadays commonly use semiautomated methods for centralized ECG interval measurement, where a trained human analyst decides whether the ECG interval annotations by the automated algorithm should be adjusted based on visual inspection of annotated waveforms on a computer screen. This approach potentially combines consistency of the automated interval measurement with the added precision of manual adjustment, although no data have been published thus far on the performance of semiautomated method.

Another important opportunity offered by digital ECGs is the possibility to perform measurements on the so-called representative beats, often simply referred to as median beats, generally available as part of the digital ECG source file. The concept of representative beats is well known in academic research for many years,¹⁰ but it has been only recently considered as a viable alternative to generate reliable and reproducible interval measurements on ECG from clinical trials that may even have advantages over the traditional CPMP-recommended approach.¹¹