1. Aetna considers signal-averaged electrocardiography experimental and investigational because no prospective clinical studies have demonstrated the utility of this testing in improving clinical outcomes.

2. Aetna considers remote algorithmic analysis of electrocardiographic-derived data (Premier Heart's Multifunction Cardiogram (MCG); also known as 3DMP Computerized EKG System) experimental and investigational because the clinical value of the system in managing persons suspected of having significant coronary artery disease has not been established.

See also CPB 0579 - T-Wave Alternans.

Signal-averaged electrocardiography (SAECG) is a technique involving computerized analysis of segments of a standard electrocardiogram that allows the detection of ventricular late potentials.  Ventricular late potentials in patients with cardiac abnormalities, especially coronary artery disease or following an acute myocardial infarction (MI), have been associated with an increased risk of ventricular tachyarrhythmias and sudden cardiac death.  Proponents of SAECG claim that it can obviate the need for invasive techniques commonly used to identify high-risk patients for interventions that treat or prevent ventricular tachyarrhythmia and sudden death.

An Agency for Healthcare Policy and Research's assessment (AHCPR, 1998) found that the current data on SAECG show relatively consistent high negative-predictive values, poor positive-predictive values, and variable sensitivity and specificity when the technique is used on patients with cardiomyopathy or following a MI.   However, the high negative- predictive value of SAECG is largely due to the fact that the incidence of fatal arrhythmic events among post-MI patients is now below 10 %.  The incidence of fatal arrhythmias has declined among post-MI patients, a large percentage of whom are on anti-thrombotic therapy, most likely following the trend of decreased mortality rate following MI.

In 1996, an American College of Cardiology (ACC) consensus statement on SAECG concluded that SAECG has “established value” in assessing the risk of development of sustained ventricular arrhythmias in patients recovering from MI.  However, subsequently published guidelines from the ACC on management of acute MI (1999) stated that the usefulness of SAECG for risk assessment after MI is less well-established by evidence/opinion.  In addition, subsequently published ACC guidelines on implantable anti-arrhythmia devices (1998) do not recommend SAECG for selecting patients for automated implantable cardioverter defibrillators (AICDs).

Although it has been proposed that SAECG may be used to select post-MI patients for anti-arrhythmic drugs or AICD implantation, there are no prospective clinical studies demonstrating the clinical utility of SAECG in selecting patients for these therapies.  In addition, there are no prospective clinical studies proving that SAECG can be used successfully to select patients for electrophysiologic studies or Holter monitoring, or to use SAECG for risk stratification in lieu of these other tests.

Grimm et al (2003) studied arrhythmia risk stratification with regard to prophylactic implantable cardioverter-defibrillator patients with in idiopathic dilated cardiomyopathy (IDC).  These researchers concluded that reduced left ventricular ejection fraction (LVEF) and lack of beta-blocker use are important arrhythmia risk predictors in IDC, whereas SAECG, baroreflex sensitivity, heart rate variability, and T-wave alternans do not seem to be helpful for arrhythmia risk stratification.  Furthermore, in a review on electrocardiographic arrhythmia risk testing, Engel et al (2004) evaluated the various electrocardiographic (ECG) techniques that appear to have potential in assessment of risk for arrhythmia.  The resting ECG (premature ventricular contractions, QRS duration, damage scores, QT dispersion, and ST segment and T wave abnormalities), T-wave alternans, late potentials identified on SAECG, and heart rate variability were explored.  The authors stated that unequivocal evidence to support the widespread use of any single non-invasive technique is lacking; further research in this area is needed.

Guidelines from the European Society for Cardiology (Brignole, et al., 2004) concluded that the systematic use of SAECG in syncope is “not recommended.”

The Premier Heart digital database-driven multi-phase (3DMP) electrocardiograph (EKG) System provides a computer analysis of digitalized 12-lead EKG waveforms in the frequency domain (power spectral estimate) to aid in the detection of significant coronary artery disease.  The 3DMP system was cleared by the FDA based on a 510(k) application.  Weiss et al (2002) reported on a cross-sectional analysis of the use of the 3DMP system in 136 patients with symptoms of potential coronary artery disease who were scheduled for angiography.  Originally, 200 patients were selected for the study, but 64 of the patients were not included in the study because of various technical problems in their 3DMP readings.

Although the 3DMP system was positive for CAD in 76 of 78 patients with greater than 60 % narrowing by angiography, the 3DMP system also read positive in 8 of 12 patients with 40 to 60 % narrowing.  None of the 10 patients with greater than 0 to 40 % narrowing read as positive by the 3DMP system, but 8 of 36 patients with 0 % narrowing read as positive for CAD.

As a significant number (2 of 78) of patients with significant angiographic lesions were missed by the 3DMP system, it is not clear that the device is sufficiently accurate to either be used in lieu of angiography or to select patients for angiography.

There are no evidence-based guidelines from national professional organizations that address the clinical utility of 3DMP in evaluating patients suspected of having coronary artery disease.  Prospective clinical studies are necessary to demonstrate the clinical utility of the 3DMP system in managing patients suspected of having significant coronary artery disease.

A technology assessment prepared for the AHCPR on ECG-based signal analysis technologies (Coeytaux, et al., 2010) stated that the reliability and test performance of 3DMP in subjects at high-risk or with known CAD is promising.  The horizon scan identified 7 potentially relevant devices, including 3 that use body surface mapping and 1 that uses mathematical signal analysis.  Of the 7 devices, only the PRIME ECG by Heartscape Technologies (body surface mapping) and the 3DMP/MCG/ mfEMT by Premier Heart (mathematical signal analysis; referred to as the 3DMP) are cleared for marketing by the FDA and commercially available.  One body surface mapping device (Visual ECG/Cardio3KG by NewCardio) is commercially available but not cleared; the other devices are not commercially available.  The assessment concluded: "There is currently little available evidence that pertains to the utility of ECG-based signal analysis technologies as a diagnostic test among patients at low to intermediate risk of CAD who present in the outpatient setting with the chief complaint of chest pain.  The limited evidence that is available demonstrates proof of concept, particularly for the PRIME ECG and 3DMP devices.  Further research is needed to better characterize the performance characteristics of these devices to determine in what circumstances, if any, these devices might precede, replace, or add to the standard ECG for the diagnosis of CAD among patients who present with chest pain in the outpatient setting.  The randomized controlled trial (RCT) study design is best suited for evaluating the impact that ECG-based signal analysis technologies may have on clinical decision-making and patient outcomes, but there are indirect approaches that might be applied to answer these questions."

Tamaki and colleagues (2009) prospectively compared the predictive value of cardiac iodine-123 metaiodobenzylguanidine (MIBG) imaging for sudden cardiac death (SCD) with that of the SAECG, heart rate variability (HRV), and QT dispersion in patients with chronic heart failure (CHF).  At entry, cardiac MIBG imaging, SAECG, 24-hr Holter monitoring, and standard 12-lead ECG were performed in 106 consecutive stable CHF outpatients with a radionuclide LVEF less than 40 %.  The cardiac MIBG washout rate (WR) was obtained from MIBG imaging.  Furthermore, the time and frequency domain HRV parameters were calculated from 24-hr Holter recordings, and QT dispersion was measured from the 12-lead ECG.  During a follow-up period of 65 +/- 31 months, 18 of 106 patients died suddenly.  A multi-variate Cox analysis revealed that WR and LVEF were significantly and independently associated with SCD, whereas the SAECG, HRV parameters, or QT dispersion were not.  Patients with an abnormal WR (greater than 27 %) had a significantly higher risk of SCD (adjusted hazard ratio: 4.79, 95 % confidence interval: 1.55 to 14.76).  Even when confined to the patients with LVEF greater than 35 %, SCD was significantly more frequently observed in the patients with than without an abnormal WR (p = 0.02).  The authors concluded that cardiac MIBG WR, but not SAECG, HRV, or QT dispersion, is a powerful predictor of SCD in patients with mild-to-moderate CHF, independently of LVEF.

Park and colleagues (2009) examined the correlation between parameters of 2-dimensional ECG and SAECG in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC).  A total of 33 patients (13 females, 40.3 +/- 14.4 years old) were included in this study.  Both the right and left ventricular dimensions and systolic function were assessed with 2-dimensional ECG.  The SAECG was performed with high-gain amplification and filtered using bi-directional Butterworth filters between 40 and 250 Hz.  The right ventricular (RV) outflow tract was the most frequently (n = 18, 54 %) involved segment.  Six (18 %) patients had only mildly decreased RV systolic function.  All the other patients had normal RV systolic function.  Although localized left ventricular wall motion abnormalities were observed in 14 (42 %) patients, the LVEF was normal in most (n = 32, 97 %).  Late potentials were positive in 22 (63 %) patients.  There was no significant correlation between parameters of the SAECG and 2-dimensional ECG for the entire patient population.  The authors concluded that the SAECG parameters exhibited no correlation to any of 2-dimensional ECG parameters in the patients with ARVC.  Fragmented electrical activity may develop with no significant relation to the anatomical changes in the patients with ARVC.

The Agency for Healthcare Research and Quality's systematic review of ECG-based signal analysis technologies for evaluating patients with acute coronary syndrome (Coeytaux et al, 2012) concluded that “Existing research is largely insufficient to confidently inform the appropriate use of ECG-based signal analysis technologies in diagnosing CAD and/or ACS.  Further research is needed to better describe the performance characteristics of these devices to determine in what circumstances, if any, these devices might precede, replace, or add to the standard ECG in test strategies to identify clinically significant CAD in the patient population of interest.  To fully assess the impact of these devices on diagnostic strategies for patients with chest pain, test performance needs to be linked to clinically important outcomes through modeling or longitudinal studies”.

Proclemer et al (2013) examined the current clinical practice of screening and risk evaluation for SCD in ischemic and non-ischemic cardiomyopathy with a focus on selection of candidates for ICD therapy, timing of ICD implantation, and use of non-invasive and invasive diagnostic tests across Europe.  A systematic screening program for SCD existed in 19 out of 31 centers (61.3 %).  Implantation of ICDs according to the inclusion criteria of MADIT-II and SCD-HeFT trials was reported in 30 and 29 % of centers, respectively, followed by MADIT-CRT (18 %), COMPANION (16 %), and combined MADIT and MUSTT (7 %) indications.  In patients with severe renal impairment, ICD implantation for primary prevention of SCD was always avoided in 8 centers (33.3%), was not used only if creatinine level was greater than 2.5 mg/dL in 10 centers (32.2 %), and in patients with permanent dialysis in 8 centers (33.3 %).  Signal-averaged electrocardiography and heart rate variability were never considered as risk stratification tools in 23 centers (74.2 %).  Implantation of a loop recorder was performed in patients with borderline indications for ICD therapy in 6 centers (19.4 %), for research purposes in 5 (16.1 %), and was never performed in 20 (64.5 %) centers.  The authors concluded that the majority of participating European centers have a screening program for SCD and the selection of candidates for ICD therapy was mainly based on the clinical risk stratification and not on non-invasive and invasive diagnostic tests or implantable loop recorder use.

Furthermore, an UpToDate review on “Clinical applications of the signal-averaged electrocardiogram: Overview” (Narayan and Cain, 2014) states that “Guideline Recommendations -- We agree with the 2008 American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Rhythm Society (HRS) scientific statement on noninvasive risk stratification and the 2006 ACC/AHA/European Society of Cardiology (ESC) guidelines for management of patients with ventricular arrhythmias, which concluded that the SAECG may be useful to identify patients at low risk for SCD, but its routine use to identify patients at high risk for SCD is not yet adequately supported.  Similarly, the 2006 AHA/ACC scientific statement on syncope concluded that routine use of T-wave alternans combined with signal-averaged ECG and assessment of heart rate variability in patients with syncope and a negative initial evaluation is not yet established and currently is not indicated”.