# Presentation: 068231

## Continuous 12-lead ECG recording

**Analysis of digital ECG data -- Public presentations**
**What can you do with the digitized ECG waveform that you cannot do with a paper ECG record?**

- Daniel B. Goodman, MD
- 	Director Medical Affairs and Scientific Innovation
- 	Covance Central Diagnostics, Covance, Inc.
- 	Reno, NV USA

## The Problem

- Are we at the limit of the information value of the QT interval for repolarization analysis?
- Better measurements of single ECGs only address methodological variation
- High biologic variation of QT and QTc is inescapable
- Need to achieve high statistical power with reasonable number of subjects
- to advance or reject compounds early
- to collect and analyze data in cost-effective manner

## Proposed Solution

- Collect data continuously to ensure detection of peak effects
- Ensure availability at times of critical drug activity: Cmax, Emax
- Collect continuously to fully characterize dose-response relationship: max tol dose
- Collect large number of data points to improve power by averaging

## Why this talk?

- “What can you do with the digitized ECG waveform that you cannot do with a paper ECG record?”
- Paper ECGs can never meet this challenge
- Continuous ECGs can never be analyzed or reviewed in a paper environment
- The FDA mandate for digital data must support this breakthrough technology

## Wide normal range of the QT

- Population reference range
- 14,379 children and adults from NHANES Study
- Males: mean QT std dev 40.1 msec (10.8%)
- Females: mean QT std dev 39.0 msec (10.4%)
- Rautaharju P, et al, Computers and Biomedical Research 1993: 26; 188-204
- Only partially addressed by rate correction

## Significant Intra-subject Variability

- Conventional 24-hour Holter data
- 21 healthy subjects
- mean intra-individual range QTc 95 msec
- std dev 20 msec
- Molnar J, et al, J Am Coll Cardiol 1996: 27; 76-83
- 12-lead ECG data
- 1300+ healthy Scottish adults
- QTc std dev 23.4 msec (5.5 %)
- MacFarlane in *Comprehensive Electrocardiology*, MacFarlane, P and Veitch Lawrie, TD, Pergamon Press London, 1989, 1442

## QTc Variability in Pharma R&D

- Does pharma R&D do any better?
- Actual experience
- Covance Central Diagnostics, unpublished data
- Single-site phase I study
- Single Cardiologist reader
- 50 volunteers on non-treatment days
- 2233 ECGs
- mean number of ECGs per subject 45
- min 17, max 54

## Mean intra-subject QTc std dev

- On all days
- 14.8 msec (3.6%)
- 95% range 8.6-21.7
- On any day (at least 7 ECGs)
- 13.3 msec (3.3%)
- 95% range 5.5-24.6
- By time of day (+/- 15 min) for subject
- 13.2 msec (3.2%)
- 95% range 4.6-25.2

## At HR of 72 bpm, one hour 4320 beats

- Standard 12-lead ECG, 10 sec = 12 beats
- typically monitored hourly in Phase I
- total data is a single QTc value
- derived from 1-3 beats
- Equivalent to sample rate of 0.7%
- Inadequate in face of unknown kinetics
- Inadequate in face of QT variability

- 12-lead ECG: Current State of Affairs

## Raymond Lipicky, MD

- DIA Meeting May 7, 2001
- “When is the best time to measure the ECG? 	CONTINUOUSLY”
- “When to measure in relationship to dosing?
- At the exact time the QTc prolongation or torsades occurs
- Who knows when that will be? That’s the reason for continuously.”

- Regulatory Encouragement

## The Technology Exists Today

- Two major US manufacturers with global distribution
- Continuous 12-lead ECG monitoring
- distinct 12-lead ECG every 10 seconds or 8 beats
- In one hour 360 - 540 values
- Well-established analysis algorithms
- Each QTc value derived from all beats
- Sampling rate 100%

## Continuous (averaged)         vs Single ECG

- Day 4

- Day 1

## Advantages

- Reliable detection of effects over entire range of recording
- Data available for retrospective scrutiny
- Cmax or QTcmax
- Permits subject-by-subject custom correction of QT for Heart Rate
- Familiar dataset at any time point
- Typical 12-lead ECG from digital data archive
- No need to extrapolate from 2- 3- channel data

## Disadvantages

- Non-standard electrode location
- BUT: does not affect QT or Heart Rate determination
- Requires automated review
- BUT: well-established and approved algorithms
- can benchmark by human readings as desired
- permits technical review to reject artifact
- large number of data points average out errors

**	**
- 	       **QTc** 		**Continuous      Single**
- 	**Inter-Subj Std Dev ****	****	****	**
- 	 	**msec** **	****   ****	****   17.1****	**** ****	****   23.4 **
- 		**Percent****	****     4.0****	****	****     5.8**
**	****Intra-Subj Std Dev ****	****	**
- 		**msec****	****	****     9.2 ****	****   14.8 ****	**
- 		**Percent**	     **2.1****	****     ****	****     3.7**
**	****	**

- Averaged Continuous vs Single ECG
- Total Treated Subjects	   48
- Total Treatment Sessions	  185
- Total Continuous ECGs    373,937
- 2,162 average values
- Total Conventional ECGs     1,108

- Phase I study - Actual experience

## Std Dev of Delta QTc’s

**	****	**
**	****        **(**msec)****	****	****Continuous  Single**
**	****Mean Delta ****	****	****2.79 **		  **7.2**
- 	**Min  ****	****	**	    **8.0****	****	****17.6**
- 	**Max  ****	****	****	****20.4****	****	****28.9**
**	****Std Dev  ****	****	****13.0 ****	****	****20.2 ****	**

- Treatment QTc- Baseline QTc
- Averaged Continuous vs Single ECG

## Power Calculation: comparison

- Subjects needed for a power of 85% in a two-way test
-  to detect a δ of 6 msec at an α of 0.05

- Power (expressed as number of subjects) is proportional to square of std dev of the deltas

## Covance Continuous Repolarization Analysis - CCRA

- Continuous 12-lead ECG recording
- Collect data continuously to ensure detection of peak effects
- Ensure availability at times of critical drug activity: Cmax, Emax
- Collect continuously to fully characterize dose-response relationship: max tol dose
- Collect large number of data points to improve power by averaging

## Further Possibilities

- Potential for additional measures using digital signal processing
- Time to 50%, 75%, 90%, 97% of total QRS-TU voltage
- Micro-volt T wave alternans
- QT/RR slope comparison
- Selective Beat Averaging
- T and U wave morphology characterization
- QTc distribution % outliers