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With significant technology advances in ECG recording through the years, the need to expand on traditional monitoring baselines-and include new variables such as time when designing clinical trial protocols-is important.
In 1949, Norman J. Holter and Joseph A. Generelli, building on previous work, described a “radiocardiogram” and a “radio-encephalograph” in the Rocky Mountain Medical Journal, thus introducing a new technology to medical science. The goal of these recordings was to “….inquire into how various bodily functions are modified by exercise, excitement, emotion, or other activity….”1
Since then, the “Holter” recording methods have been improved by advances in miniaturization and recording technologies. The state-of-the-art in recording media has gone from magnetic tape to digital storage, with some recordings being transmitted to central processing centers using Bluetooth technologies, making almost real-time analysis possible. And, in the last decade, technology has advanced to the point where multiple-day recordings are possible.
Use of single-day recordings reached its zenith prior to the publication of the Cardiac Arrhythmia Suppression Trial (CAST) findings. CAST tested the hypothesis that suppression of ventricular arrhythmias as seen on Holter recordings in patients with myocardial infarction would decrease mortality. The CAST study showed an increased mortality with treatment as opposed to placebo.2 After the CAST findings were announced, however, the use of Holter recordings was dramatically reduced, as the need for finding simple ventricular arrhythmias was attenuated.
Up to this point, single-day data yielded a false sense of safety or concern, possibly because, as DiMarco noted, of the considerable day-to-day variability of arrhythmia and myocardial ischemia.3 The evanescent nature of arrhythmias was described by Corday, who compared a 10-hour Holter recording with a “conventional ECG”.4 What we have come to know about “normal” has evolved over the years as recording times have increased.
The traditional way to describe “normal” on Holter recordings is to explain the abnormalities encountered. This includes any single or run of ectopic beats, rhythms, and sometimes included an ST-segment analysis or, more rarely, a QT-interval analysis. Judgments were made based on these ectopic counts and waveform descriptions. Additionally, normal healthy subjects might manifest benign arrhythmias not seen in other populations. These confounders make any description of “normal” difficult.
As technology improved, recording periods were sometimes prolonged to two or three days. Now, technology has advanced even further and recordings can be taken over weeks or months. It is, once again, time to rethink “what we know.”
One of the challenges for those who write clinical trial protocols is to collect enough data to ensure that evanescent arrhythmias are not considered “drug-related.” This will most likely be done in two ways: 1) over-collection of screening and baseline data, 2) redevelopment of normal ranges.
Due to the expense of clinical trials, cost-cutting has become very important in the drug-development process. The risk of cutting costs is that we collect homogenous data, and infrequent, otherwise unimportant abnormalities might take on an unwarranted significance. Indeed, the goal is to avoid “problematic” data, or data that might be considered an adverse event. An alternative to collecting limited data is to over-collect baseline data. Certainly, if we have 30 days of Holter data at baseline, we might be in a better position to determine a subject’s “normal” profile.
From long-term data sets, new normal ranges can be developed. If it’s known that sinus pause of three seconds or 5-beat runs of VT are not uncommon, perhaps seeing these events in the drug-development process would not be considered an adverse event warranting further, expensive follow-up. The logical extreme is that some good drugs might not be killed in the development process.
To conclude, technology has advanced enough that Holter’s original vision can be expanded to include time as a new variable. As technology changes, so must the prism of our analysis. What we thought was abnormal might now be considered normal or at least a normal variant. We need to collect more robust data to answer these questions.
Timothy Callahan, PhD, is Chief Scientific Officer, Biomedical Systems; Joseph Pierro, MD, is Chief Medical Officer, Biomedical Systems
1. Holter NJ, Generelli JA. Remote Recording of Physiologic Data by Radio. Rocky Mountain Medical Journal. September 1949. 747-751.
2. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary Report: Effect of Encainide and Flecainide on Mortality in a Randomized Trial of Arrhythmia Suppression after Myocardial Infarction. N Engl J Med 1989; 321:406-412.
3. DiMarco JP, Philbrick JT. Use of ambulatory electrocardiographic (Holter) monitoring. Ann Intern Med. 1990 Jul 1;113(1):53-68.
4. Corday E, Bazika V, Lang TW, Pappelbaum S, Gold H, Bernstein H. Detection of Phantom Arrhythmias and Evanescent Electrocardiographic Abnormalities. JAMA 1965: 193(6); 79-83.