National Coverage Analysis (NCA) Proposed Decision Memo

Microvolt T-wave Alternans


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Decision Summary

The Centers for Medicare & Medicaid Services has decided that no National Coverage Determination (NCD) is appropriate at this time for microvolt T-wave alternans (MTWA) testing using the modified moving average (MMA) method for the evaluation of patients at risk for sudden cardiac death (SCD).  National non-coverage will be removed. Medicare coverage of MTWA using the MMA method will be determined by the local contractors.

Proposed Decision Memo

To:		Administrative File: CAG #00293R2 
		Microvolt T-wave Alternans 
From:	Tamara Syrek Jensen, JD 
		Director, Coverage and Analysis Group 
		Joseph Chin, MD, MS 
		Acting Deputy Director, Coverage and Analysis Group 
		James Rollins, MD, PhD 
		Division Director 
		Kim Long, BA 
		Lead Analyst 
		Joseph Dolph Hutter, MD, MA 
		Medical Officer 
Subject:		Final Decision Memorandum: Microvolt T-wave Alternans  
Date:		January 13, 2015

I. Final Decision

The Centers for Medicare & Medicaid Services has decided that no National Coverage Determination (NCD) is appropriate at this time for microvolt T-wave alternans (MTWA) testing using the modified moving average (MMA) method for the evaluation of patients at risk for sudden cardiac death (SCD). National non-coverage will be removed. Medicare coverage of MTWA using the MMA method will be determined by the local contractors.

II. Background

A. Sudden Cardiac Death

SCD is generally defined as a sudden and unexpected pulseless event due to an underlying primary cardiac event (Chugh 2004, Myerburg 1994). A National Institutes of Health (NIH) work group has provided operational definitions for established and probable SCD (NIH workshop 2009, Fishman 2010). An established case of SCD is an unexpected death without an obvious extra-cardiac cause and which occurred rapidly while being witnessed or within one hour of symptom onset if unwitnessed. A probable case of SCD is an unexpected death without an obvious extra-cardiac cause and which occurred within the previous 24 hours. SCD can present as ventricular tachycardia (VT), ventricular fibrillation (VF), bradyarrhythmia, asystole, or pulseless electric activity (PEA; previously called electromechanical dissociation or EMD).

SCD claims 250,000 to 350,000 lives in the United States annually (Lloyd-Jones 2010) with an annual incidence of 50 to 200 per 100,000 in the general population (Albert 2003, Byrne 2008, Chugh 2004, Cobb 2002, de Vreede-Swagemakers 1997, Escobedo 1996, Gillum 1989, Juntilla 2010, Kong 2011, Nichol 2008, Roger 2011, Vaillancourt 2004, Zheng 2001). Although by some estimates, U.S. incidence rates may have declined over time, they remain higher than in Mediterranean countries (Marrugat 1999, Masiá 1998). Ischemic heart disease accounts for approximately 80% of SCD cases in the U.S. (Myerburg 2001) versus about 60% in Mediterranean countries (Subirana 2011). Despite the decline in age-adjusted coronary heart disease mortality, approximately 50% of deaths from coronary heart disease qualify as SCD (Huikuri 2001, Fox 2004). It’s been noted that 40% or more of SCD occurs in those less than 65 years of age and that the majority of SCD events (absolute number) occur in the general population or in the population with no prior cardiac history, but with risk factors for cardiac disease (Chugh 2004, Myersburg 1992). Implantable cardioverter defibrillator (ICD) therapy has been shown to reduce mortality in those who have been resuscitated from near-fatal ventricular arrhythmias and in those who have ischemic or non-ischemic dilated cardiomyopathy, reduced left ventricular ejection fraction and heart failure (see our NCD for Implantable Automatic Defibrillators in Section 20.4 of the NCD Manual).

B. Electrical Activity of the Heart and T-waves

Electrical activity of the heart can be assessed using the electrocardiogram (ECG).

Beat-to-beat changes in the contour, amplitude, or polarity of the T-wave were first described by Hering in 1908. The clinical significance of such T-wave alternans remained unknown until Schwartz et al. observed that the T-wave configuration in a patient with syncope and long Q-T syndrome changed with stress and/or physical activity (Schwartz 1975). Changes in T-wave morphology were generally not detectable by visual inspection of the ECG, but these micro T-wave variations could be computed from the power spectrum of the T-wave fluctuations (Adam 1984).

C. Methods of MTWA Detection

Several methods to detect these T-wave changes have been developed (Martinez 2005). All methods need to (1) locate the T-wave signal by defining a T-wave window, (2) adjust for variation in the baseline of the signal, (3) filter out noise, and (4) align the series of T-waves for superimposition and analysis. Two methods have been approved by the Food and Drug Administration (FDA): the fast-Fourier-transformation spectral analysis (SA) method (Cambridge Heart) and the modified moving average (MMA) method (GE Medical Systems).

III. History of Medicare Coverage

A. Prior Requests

CMS has previously reviewed the scientific literature for MTWA as a diagnostic test for Medicare beneficiaries at risk of SCD. On March 21, 2006, we established national coverage for MTWA using the SA methodology only. That NCD was based on the SA method’s predictive value of who was thought to not likely benefit from ICD therapy (

Subsequently, we were asked to reconsider the NCD specifically to reverse non-coverage of MTWA with the MMA method. On May 12, 2008, we determined that there was insufficient evidence to conclude that use of MTWA testing with the MMA method would lead to improved health outcomes for Medicare beneficiaries at risk for SCD ( AgAAAA%3d%3d&).

B. Current Request

GE Healthcare has formally requested that CMS reconsider the current MTWA NCD to broaden national coverage to include use of the MMA method as an alternative to the already approved SA method for MTWA testing.

C. Benefit Category

Medicare is a defined benefit program. An item or service must fall within a benefit category as a prerequisite to Medicare coverage §1812 (Scope of Part A); §1832 (Scope of Part B) and §1861(s) (Definition of Medical and Other Health Services) of the Act. MTWA using the MMA method is considered to be within the following benefit category: other diagnostic tests, §1861(s)(3) of the Act. This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service.

IV. Timeline of Recent Activities

Date Action
April 23, 2014 CMS accepted a formal request for reconsideration of the NCD Manual Section 20.30 to include the MMA method of determining MTWA. We posted a tracking sheet on our web site and the initial 30 day public comment period commenced.
May 23, 2014 The initial 30 day public comment period ended. Seventeen comments were received.
October 23, 2014 Proposed decision posted.
November 24, 2014 The second 30 day public comment period ended. Eighteen comments were received.
January 13, 2015 Final decision posted.

V. FDA Status

The FDA has cleared two methods of MTWA testing through the 501(k) process: Cambridge Heart’s spectral analysis (SA) method and General Electric’s modified moving average (MMA) method. While the focus of this National Coverage Analysis (NCA) is the MMA method, we discuss both devices when we think it will be helpful for the reader.

GE’s Modified Moving Average Method

The FDA cleared GE’s initial device for MTWA testing using the MMA method on December 3, 2002 (K023380;, and cleared the associated algorithm software on October 30, 2003 (K032513;

The latter clearance document states:

“The T-Wave Alternans (TWA) Algorithm Option is intended for use in a hospital, doctor's office or clinic environment by competent healthcare professionals for recording ST-T wave morphology fluctuations for patients who are undergoing cardiovascular disease testing. T-Wave Alternans (TWA) describes an electrocardiographic (ECG) pattern that exhibits different ST/T-wave morphologies on alternating beats. The algorithm performs the measurement of this variation at an accuracy and resolution of 1-microvolt. The TWA Algorithm Option permits visual confirmation of TWA by displaying the original ECG along with representative complexes made from a moving average of every other beat.

The TWA Algorithm measurements have been found to be predictive of arrhythmic death and can be used for the purposes of risk stratification. The TWA Algorithm Option allows the user to specify the maximal heart rate for valid TWA measurements and the specific heart rate to be attained before TWA is measured. The TWA Algorithm Option is intended to provide only the measurements of the fluctuations of the ST-T-waves. TWA measurements are intended for qualified personnel in evaluating the patient in conjunction with the patient's clinical history, symptoms, other diagnostic tests, as well as the professional's clinical judgment. No interpretation is generated.”

The FDA cleared an ancillary digital ambulatory ECG recorder on September 2, 2005 (K042782;

Cambridge Heart’s Spectral Analysis Method

The FDA cleared high-resolution, noise-reducing ECG electrodes (K962115, 8/29/1996, and K002230, 8/18/2000) and the initial versions of the CH 2000 Cardiac Diagnostic System to collect and record electrocardiographic data (CH 2000 Stress Test System, K950018, 2/29/1996 and CH 2000 Cardiac Diagnostic System [modified], K981697, 10/14/1998,

The FDA cleared the first computer processing system for T-wave alternans as a system that measured T-waves without other ECG components (K001034, 6/9/2000) and then as HearTwave (K003492, 1/18/2001). The latter clearance document states:

“The Alternans Processing System used with the Analytic Spectral Method of Alternans Processing is intended for the measurement of Microvolt T-wave Alternans at rest and during ECG stress testing.
The presence of Microvolt T-wave Alternans as measured by Analytic Spectral Method of Alternans Processing in patients with known, suspected or at risk of ventricular tachyarrhythmia predicts increased risk of a cardiac event (ventricular tachyarrhythmia or sudden death).
The Analytic Spectral Method of Alternans Processing should only be used as an adjunct to clinical history and the results of other non-invasive and/or invasive tests.
The predictive value of T-wave Alternans for cardiac events has not been established in patients with active untreated ischemia.
Microvolt T-wave Alternans is defined by T-wave Alternans, which is

a) measured by high resolution sensors,
b) is present in leads X,Y, Z, VM or two adjacent precordial leads,
c) is at the level of 1.9 microvolts after signal optimization and subtraction of the background noise level,
d) is at least three standard deviations greater than the background noise level,
e) is present at rest or has an onset heart rate of below 110 beats per minute, and
f) is sustained at heart rates above the onset heart rates.”
“The Alternans Processing System works in conjunction with a host standard-stress ECG controller. In the Cambridge Heart Model CH 2000 Cardiac Diagnostic System, the host controller is integral to the device (K983102)... The Alternans test using the Alternans Processing System is performed with seven standard stress test electrodes and seven proprietary multi-segment Micro-V Alternans Sensors.”

In a later clearance document (K012206, 10/12/2001,, the computer processing system was reported to have utility “at rest and during treadmill, ergometer, electrophysiological, and pharmacologic testing” and that the system uses interpretive Alternans Report Classifier software that provides an assessment of the alternans report data to assist the physician in diagnosis. The computerized assessment is printed at the bottom of the alternans report and indicates that the result is consistent with Positive, Negative, or Indeterminate finding.”

This processing system was more fully integrated into the Cambridge devices for collecting and recording electrocardiographic data in subsequent clearances.

VI. General Methodological Principles

When making national coverage determinations (NCDs), we evaluate relevant clinical evidence to determine whether the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member consistent with §1862(a)(1)(A). This evaluation helps determine whether: (1) the specific assessment questions can be answered conclusively; and (2) the intervention is likely to improve health outcomes for beneficiaries. An improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary.

A detailed account of the methodological principles of study design we use to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix A.

Public commenters sometimes cite the published clinical evidence and provide us with useful information. Public comments that provide information based on unpublished evidence, such as the results of individual practitioners or patients, are less rigorous and therefore less useful for making a coverage determination. We use the initial comment period to inform the public of our proposed decision. We then respond in detail to the public comments about the proposed decision when we issue our final decision memorandum.

VII. Evidence

A. Introduction

The evidence reviewed includes the published medical literature on pertinent clinical studies using the MMA method for MTWA testing.

B. Discussion of Evidence Reviewed

1. Key Question

Is the evidence sufficient to conclude that MTWA testing using the MMA method improves health outcomes for Medicare beneficiaries who are candidates for ICD placement?

2. External Technology Assessments

CMS did not request an external technology assessment (TA) on this issue.

3. Internal Technology Assessment

Our evidence review included: (1) articles and reports submitted by the requestor as well as those obtained by searching literature and technology review databases from PubMed, EMBASE, the Agency for Healthcare Research and Quality (AHRQ), the Blue Cross/Blue Shield Technology Evaluation Center, Cochrane, and the National Institute for Health and Care Excellence (NICE); (2) FDA assessments and surveillance reports; (3) NIH workshop proceedings; and (4) published professional society commentary (which ranged from informed opinion to formal evidence-based analysis). We excluded oral presentations, unpublished white papers, abstracts, case reports, non-English publications and studies with fewer than 100 patients to ensure that studies were peer-reviewed and sufficiently powered. CMS also searched to help identify relevant clinical trials.

i. Requestor Submission

To support its request for coverage, the requestor initially submitted 32 papers as PDFs or bibliographic citations.

ii. CMS Literature Search Terms

The search terms used by CMS were:
a. Sudden cardiac death, cardiac arrest, resuscitation, and syncope.
b. T-wave alternans alone or combined with arrhythmia, anti-arrhythmic drugs, ß-blockers, cardiac defibrillator, cardiomyopathy/cardiac myopathy, dysrhythmia, ejection fraction, fibrillation, heart failure, implantable cardioverter defibrillator (ICD), infarction, primary prevention, risk stratification, sudden (cardiac) death, ventricular tachycardia, Alternans Before Cardioverter Defibrillator (ABCD), Multicenter Automatic Defibrillator Implantation Trial II (MADIT II), Microvolt T Wave Alternans Testing for Risk Stratification of Post MI Patients (MASTER), Risk Estimation Following Infarction, Noninvasive Evaluation (REFINE), and Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT).

iii. CMS Search Results

Our goal was to find clinical trials that linked diagnostic results of the MTWA test using the MMA method with the selection of a therapeutic intervention that improved health outcomes – especially for those at risk of SCD. Based on the search methods and inclusion and exclusion criteria stated above, we found 21 publications constituting 14 unique clinical studies. The investigators of The Finnish Cardiovascular Study (FINCAVAS) presented serial data on an ever-larger patient cohort accrued over time (Leino 2009, Leino 2011, Minnikinen 2009, Nieminen 2007, Slawnych 2009). Surgit evaluated patient populations in two studies that appeared to overlap (Surgit 2014a, Surgit 2014b). One publication is an ancillary analysis of combinations of previously published studies (Slawnych 2009).

Patient Populations

Investigators evaluated the utility of MTWA testing in a variety of patient populations. This included community dwelling geriatric patients, and patients with myocardial infarction, left ventricular dysfunction including heart failure, congenital heart disease, or hypertension.

Study Design

There were no randomized controlled trials. Study designs were prospective, retrospective or cross-sectional analyses. Blinding, where present, was limited to those interpreting test results or adjudicating causes of death. Six studies used controls. Of these, four used matched controls (Kenttä 2014, Nieminen 2014, Stein 2008, Stein 2010), one used a cohort control (Li-na 2012), and one study used normal subjects as controls (Trojinarska 2014).

The remaining studies conducted intra-group comparisons. Six studies compared differences in clinical outcomes on the basis of T-wave alternans status (Exner 2007, FINCAVAS series, Hoshida 2013, Yu 2012, Kim 2014, Sakaki 2009). Six studies compared the differences in the likelihood of aberrant T-wave alternans on the basis of the presence or absence of dysrhythmic outcome or death (Arisha 2013, FINCAVAS series, Kim 2014, Sulimov 2012, Sakaki 2009, Yu 2012).

Three of the studies with matched controls divided patients on the basis of clinical outcomes (Nieminen 2014, Stein 2008, 2010). Four publications (with three unique study populations) described differences in MTWA by patient cohort (Li-na 2011, Surgit 2014a, Surgit 2014b, Trojinarksi 2014) but did not provide hard outcomes.

Study Endpoints

Investigators used a variety of primary endpoints:

  • SCD alone or in combination with any of the following: cardiac arrest/resuscitation, cardiac death, all-cause mortality, PVCs, sustained ventricular tachycardia, or ventricular fibrillation (Arisha 2013, Yu2012);
  • cardiac death alone or in some combination with cardiac arrest or resuscitation, or all-cause mortality (Exner 2007, Hoshida 2013, Li-na 2012, Sakaki 2009, Slawnych 2009);
  • death alone or in combination with transplantation (Kim 2014, Stein 2010);
  • change in MTWA status (Kenttä 2014);
  • MTWA status in those with SCD, cardiac death, or all-cause mortality (Nieminen 2014, Stein 2008);
  • differences in MTWA status (Li-na 2011, Surgit 2014a, Surgit 2014b, Trojinarksa 2014).

For some studies, the primary endpoint was not clearly stated:

  • in their review of post-exercise T-wave alternans test results from the REFINE and FINCAVAS studies, Slawnych et al. delineated both all-cause mortality and cardiovascular mortality as the primary endpoint (Slawnych 2009);
  • in the FINCAVAS study series, the publications Leino 2011, Nieminen 2007, Minkkinen 2009 used SCD, cardiovascular death and all-cause as primary endpoints, and Leino 2009 publication used cardiovascular death and all-cause mortality as primary endpoints;
  • in the Nieminen 2014 publication, endpoints included SCD, cardiovascular death, all-cause death, and four or eight beat series of ventricular tachycardia on day one of hospitalization.

Study Results

Eight investigator groups using a variety of endpoints reported positive results supportive of MTWA use in their longitudinal clinical studies:

  • Hoshida 2013, post myocardial infarction, n=313, mean age=70 years, LVEF=47%;
  • Leino 2011, referred for exercise study, n=3598, mean age=55.6 years, LVEF not reported;
  • Li-na 2012, myocardial infarction, n=96 cases, , 75 controls, mean age=65 years in cases, LVEF=45% or higher;
  • Sakaki 2009, mixed ventricular dysfunction, n=295, mean age=66 years, LVEF=34%, case-control;
  • Stein 2008, post myocardial infarction, n=92 cases, 46 controls, mean age=66 years, LVEF=34% in cases;
  • Stein 2010, healthy community dwelling, n=, 49 cases, 98 controls, mean age=73 years, LVEF normal in 108 participants;
  • Sulimov 2012, post myocardial infarction, n=111, mean age=64.1 years, mean LVEF=46.6%.
  • Yu 2012, post myocardial infarction 1-15 days, n=227, mean age=56 years, LVEF≥35% in 199 patients;

Three investigator groups reported mixed results regarding the utility of MTWA:

  • Exner et al. reported positive results when MTWA testing was conducted 10 to 14 weeks after myocardial infarction, but negative results when testing was conducted 2 to 4 weeks post myocardial infarction; n=322 (Exner 2007). Both MMA and SA data were apparently collected but a comparative analysis was never reported.
  • Nieminen et al. reported equivocal results in patients with non-ST segment elevation acute coronary syndrome. Elevated MTWA values were linked with total mortality, but not with SCD or total cardiac mortality in a sub-analysis of a drug therapy trial potentially confounding the findings (Nieminen 2014).
  • Kenttä et al. reported small reductions in MTWA levels, but no reductions in cardiac mortality, after a two-year exercise program for patients with angiographically-confirmed coronary artery disease (Kenttä 2014).

Three investigator groups reported negative results for their clinical trials:

  • Arisha et al. reported that different MTWA power results depending on the channel and that result predicted outcomes (Arisha 2013). The investigators also noted that heart rate turbulence was a predictor of outcomes, and the accuracy of this measure improved when combined with MTWA and left ventricular function.
  • Kim et al. reported that MTWA results did not predict all-cause mortality or cardiac transplantation (Kim 2014).
  • Li-na et al. reported higher MTWA power levels in patients with diabetes and a history of myocardial infarction than in patients without diabetes but with a history of myocardial infarction. The combination of heart rate turbulence and MTWA status predicted future cardiac mortality (li-na 2012).

Review Summary

Of the 21 publications found 14 were unique clinical studies. Of these, 10 studies reported positive results. There were no randomized controlled trials. Only the FINCAVAS series studied greater than 500 patients. Only two studies (one positive, one negative) used SCD or resuscitated cardiac arrest as a primary endpoint. No studies assessed MTWA testing in patient populations limited to the type in which ICD therapy has been demonstrated to reduce mortality. Although the focus of our evidence review was on the MMA method, we did search for prospective, head-to-head trials comparing SA with MMA, and found none.


A Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) meeting was not convened on this issue.

5. Evidence-based Guidelines

a. (2010) Sudden Cardiac Death Prediction and Prevention Report from a National Heart, Lung, and Blood Institute and Heart Rhythm Society Workshop
Fishman et al. 2010

“In contrast to invasive electrophysiological testing, noninvasive tests for predicting SCD are clearly more attractive in a clinical strategy for widespread screening. Numerous markers derived mainly from surface ECG have been correlated with SCD, cardiac, and total mortality over the past 3 decades. These can be classified as (1) indices of abnormal autonomic modulation of cardiovascular function such as heart rate variability, heart rate turbulence, heart rate recovery from exercise, and baroreflex sensitivity; (2) indices of abnormal impulse conduction such as signal averaged ECG and QRS fractionation; and (3) indices of abnormal repolarization such as microvolt T wave alternans, QT interval dynamicity, and various measures of T wave morphology and dispersion.

Most of the autonomic markers have been correlated with total rather than arrhythmic mortality. Although extensive comparative data are not available, when examined in the same population with other risk markers T wave alternans appear to predict SCD-related events with greatest negative predictive value, suggesting that a patient with systolic dysfunction and a negative T wave alternans test may be at comparatively low risk for events. However, other recently published data from 2 large clinical trials of the prophylactic ICD indicate that the use of T wave alternans is likely to be limited by low predictive ability, higher number of indeterminate tests, and concern about incremental value over known risk factors. Taken together, the available experience suggests that multiple risk markers used in combination may provide a more robust prediction of events, which is not surprising when one considers the complexity and diversity of electro-anatomic substrates that underlie SCD.” To date, no randomized clinical trials have been conducted that demonstrate benefit of non-invasive risk stratification in reducing SCD events.

However, the overwhelming majority of SCDs occurs in the general population, and approximately 55% of men and at least 68% of women have no clinically recognized heart disease prior to SCD.

Current methods to differentiate patients at highest risk for arrhythmic death from all-cause death are insufficient and lack robustness in guiding the use of ICD therapy. Data on SCD risk are best developed in patients with moderate or severe LV dysfunction either after MI or with chronic ischemic or nonischemic cardiomyopathies. Although patients without severe systolic dysfunction are at lower individual risk, many sudden deaths occur in such patients. Strategies for effective risk stratification in these moderate risk populations should be investigated. The optimal approaches for combining potential risk factors to identify individuals at risk and to target risk factors for treatment have not been determined.

b. (2011) Microvolt T-Wave Alternans: Physiological Basis, Methods of Measurement, and Clinical Utility—Consensus Guideline by International Society for Holter and Noninvasive Electrocardiology (Cosponsored by the Japanese Circulation Society, the Computers in Cardiology Working Group on e-Cardiology of the European Society of Cardiology, and the European Cardiac Arrhythmia Society) Verrier et al. 2011

“In their meta-analysis, Hohnloser et al. proposed a clinical algorithm to identify patients who would not benefit from ICD implantation for primary prevention (see their Fig. 2.) Their analysis revealed that the mortality rate of TWA negative patients with LVEF <=35% but no history of ventricular arrhythmias and no prior ICD implantation was 4-fold lower than that of MADIT II or SCD-HeFT trial patients randomized to ICD therapy. Accordingly, the negative predictive value derived for this group is >99%. This algorithm will require testing in a prospective trial.”

“Interventional trials, which have been performed to date only with the Spectral Method, have not demonstrated that a negative TWA test result can sufficiently guide decision-making with regard to ICD implantation.”

“...Frontiers of TWA research include use in arrhythmia risk stratification of individuals with preserved ejection fraction, improvements in predictivity with quantitative analysis, and utility in guiding medical as well as device-based therapy. Overall, although TWA appears to be a useful marker of risk for arrhythmic and cardiovascular death, there is as yet no definitive evidence that it can guide therapy.”

6. Professional Society Position Statements

The International Society for Holter and Noninvasive Electrocardiology (ISHNE) submitted a position statement during the proposed NCD comment period. The statement endorses MMA analysis of TWA for sudden cardiac death risk stratification. They state that their decision to endorse the MMA method is based directly on the evidence provided in the 2011 TWA Consensus Guideline, which was sponsored by ISHNE and prepared by an official writing committee in collaboration with experts in both the SA and MMA methods.

7. Systematic Reviews

Quan X, Zhou H, Ruan L, Lv J, Yao J, Yao F, Huang K, Zhang C. Ability of ambulatory ECG-based T-wave alternans to modify risk assessment of cardiac events: a systematic review BMC Cardiovasc Disord. 2014 Dec 20;14(1):198. PMID: 25528490

Quan and colleagues reported the results of a “systematic review and meta-analysis to determine the utility of 24-hour Holter AECG-based TWA for risk stratification of cardiac events in a wide variety of patient populations.” Authors searched from January 1990 to November 2014. Inclusion criteria were: “1) prospective clinical study of ≥ 100 human subjects; 2) 24-hour Holter AECG-based TWA obtained with daily activity; 3) reported meaningful clinical endpoints including SCD, cardiac mortality, and/or ventricular arrhythmias; 4) provided clear definition of positive or negative TWA.” Five studies with a total of 1588 participants (mean age 64 years; 74% were men) met inclusion and were analyzed.

The authors found: “Compared with the negative group, positive group showed increased rates of SCD (hazard ratio [HR]: 7.49, 95% confidence interval [CI]: 2.65 to 21.15), cardiac mortality (HR: 4.75, 95% CI: 0.42 to 53.55), and composite endpoint (SCD, cardiac mortality, and severe arrhythmic events, HR: 5.94, 95% CI: 1.80 to 19.63). For the 4 studies evaluating TWA measured using the modified moving average method, the HR associated with a positive versus negative TWA result was 9.51 (95% CI: 4.99 to 18.11) for the composite endpoint.” They concluded: “The positive group of AECG-based TWA has a nearly six-fold risk of severe outcomes compared with the negative group. Therefore, AECG-based TWA provides an accurate means of predicting fatal cardiac events.”

Verrier RL, Malik M. Quantitative T-wave alternans analysis for guiding medical therapy: an underexploited opportunity. Trends in Cardiovascular Medicine, in press.

8. Public Comments

Initial Comment Period: April 23, 2014 – May 23, 2014

CMS received 17 timely public comments during the first public comment period. Thirteen of these comments supported expanding CMS coverage to include the MMA method of MTWA testing. They stated that it is advantageous to cover both options since they provide complimentary results. One comment supported CMS considering alternatives to the SA method but did not directly comment on the MMA method. Three comments did not support coverage of the MMA method. They stated that there is a lack of prospective data and that no new clinical data has become available since the last reconsideration.

Of the 17 comments received, four were from cardiologists, four were from professors of medicine, two were from professors of cardiology, one was from a professor of biomedical engineering, two were from medical directors (one for clinical research and the other for a lab that tests heart rate variability (HRV)), one was from (a European news website), one was from the requestor, one was from the manufacturer of the SA method, and one was an individual who did not identify with an associated organization or profession. Several of the comments cited references, many of which we had already reviewed. The additional references were considered in our evidence review for the proposed NCD.

Second Comment Period: October 23, 2014 – November 24, 2014

During the second comment period, 18 timely comments were received. All of the comments opposed the proposed NCD. All the comments were in support of expanding CMS coverage to include the MMA method of MTWA testing. All, but a single commenter, were cardiologists or experts in the field of cardiology. Ten commenters were authors of papers cited in the proposed decision memorandum (PDM). One of the commenters, a co-inventor of the MMA method submitted two comments. Four of the commenters were authors of the 2011 Consensus Guideline on Microvolt TWA. One commenter was another co-inventor of the MMA method. One commenter was the Chief Scientist representing the requestor. In addition, the Officers and Board of Trustees of the International Society for Holter and Noninvasive Electrocardiology (ISHNE) submitted a comment to endorse the MMA method of MTWA for sudden cardiac death risk stratification. Many of the commenters cited references that were either in the PDM or in the previous NCDs on MTWA. One new study that is in press was referenced.

Comment: Many commenters stated that the PDM mischaracterized the 2011 TWA Consensus Guideline published in the Journal of the American College of Cardiology as only supporting the SA method and, therefore, suggest that we drew a wrong conclusion that there were no guidelines that specifically focus on MMA or compared MMA to SA. The commenters, including a few that co-authored the guidelines, emphasized that this guideline was written by an international panel of experts in both methods and was sponsored by four international societies. The authors argue that the TWA Consensus Guideline provided a balanced discussion of both SA and MMA methods of MTWA and issued guidelines for their appropriate use. The commenters also pointed out that ISHNE endorsed the MMA method based on these guidelines in which they were a co-sponsor.

CMS Response: We appreciate experts in the field of cardiology providing us with their insight on how the TWA Consensus Guideline provides information on the MMA method as well as SA. We have revised our analysis based on new evidence and a reanalysis of the specific studies mentioned by commenters (please see revised analysis section). Based on this additional information and evidence, CMS has decided not to move forward with a national non-coverage determination for MTWA using the MMA methodology but will allow the coverage of MTWA using the MMA method under section 1862(a)(1)(A) to be determined by local contractors. Contractors may make these determinations on either a case-by-case basis or by developing a local coverage determination.

Comment: The International Society for Holter & Noninvasive Electrocardiology (ISHNE) submitted their endorsement of the MMA method. They base their endorsement directly on the evidence provided in the TWA Consensus Guidelines.

CMS Response: We appreciate their comments and the “Professional Society Position Statement” section of this final decision has been updated to include their endorsement of the MMA method.

Comment: Many commenters mentioned that appropriate guidelines for the MMA method are not only stated in the 2011 TWA Consensus Guideline but also in the TWA Physicians Guide, which is distributed with the FDA-cleared software.

CMS Response: We appreciate the comment. CMS has decided not to move forward with a national coverage determination and allow the section 1862(a)(1)(A) coverage determination for MTWA using the MMA method to be determined by local contractors.

Comment: Many of the commenters clarified that the American Heart Association/American College of Cardiology/European Society of Cardiology 2006 recommendation endorses the use of ambulatory as well as exercised-based TWA for arrhythmia risk evaluation. This guideline granted a Class I, Level of Evidence: A “to evaluate risk or to judge therapy” and a Class IIa, Level of Evidence: A “improve diagnosis and risk stratification of patients with ventricular arrhythmias who are at risk for developing life-threatening ventricular arrhythmias” classification to TWA monitoring with ambulatory ECG. Further, the commenters pointed out that MMA is the only FDA-approved method available for use with ambulatory ECG.

CMS Response: Thank you for the comment. We appreciate the clarification and have taken this into consideration in our reanalysis.

Comment: Many of the commenters expressed that the MMA method is generalizable to the Medicare population. They point out that unlike the SA method; the MMA method does not require a target heart rate or an exercise test. They state that Medicare patients generally have more frequent locomotor dysfunction, poor limb perfusion, and other disabilities and /or comorbidities. They further state that patients do not need to be excluded from the test on the basis of inability to perform an exercise test as a result of these conditions and therefore the utility of MMA-based TWA with ambulatory ECG monitoring becomes useful with this population.

CMS Response: Thank you for the comment. We have updated our analysis to include all new evidence. CMS has decided not to move forward with a national non-coverage determination for MTWA using the MMA methodology but will allow the coverage of MTWA using the MMA method under section 1862(a)(1)(A) to be determined by local contractors (please see revised analysis section).

Comment: An investigator for a study cited in the PDM submitted a comment to answer a question raised in the PDM. The question was raised “whether or not the individual who analyzed TWA levels was blinded regarding clinical outcomes,” in the 2009 Sakaki study. The commenter clarified that the “individual who analyzed TWA levels was blinded regarding clinical outcomes” and therefore goes on record stating that there was no opportunity for bias in declaring the TWA values.

CMS Response: Thank you for the comment. We appreciate the clarification and have modified the description in the evidence section.

Comment: Many of the commenters opposed Medicare covering one method but not the other.

CMS Response: We appreciate the comment. CMS has decided not to move forward with a national non-coverage determination for MTWA using the MMA methodology but will allow the coverage of MTWA using the MMA method under section 1862(a)(1)(A) to be determined by local contractors.

Comment: One commenter submitted a comment in response to another comment received during the initial comment period. The commenter offered a response to what he claims to be inaccurate claims made in that submitted comment and suggested that the MMA method provided a granularity of information that was important for clinicians and patients

CMS Response: Section 1862(l) of the Social Security Act establishes an open and transparent process that enables the public to submit information and evidence concerning the items and services that CMS is evaluating for a potential national coverage determination. The public process often leads to diverse opinions about particular items and services. We appreciate that the public comment period provides an opportunity for commenters to exchange ideas and information on scientific matters that helps our agency to make the most appropriate decisions based on the available scientific evidence.

Comment: One commenter stated that we need keep in mind the importance of preventive medicine.

CMS Response: While we appreciate the comment, this national coverage analysis concerns coverage of a particular diagnostic test, not a preventive service.

Comment: A few commenters stated that the cost efficiency of the MMA method should be considered.

CMS Response: CMS does not consider cost in evaluating evidence in making NCDs.

Comment: One commenter stated that approximately 40 cardiologists in their area have access to the SA method of TWA analysis but none of them continue to use this modality when treating patients at risk for SCD. The commenter suggested a number of reasons for the discontinuance of the SA method.

CMS Response: While we appreciate the comment, the scope of this NCD concerns the MMA method. We note that the SA method is covered under our NCD at section 20.30 of the Medicare National Coverage Determinations Manual.

Comment: The requestor submitted a comment pointing out (and listing by name) that world leaders in the field of SCD risk stratification and individuals who have established the guidelines for ICD implantation had written in support of the MMA method.

CMS Response: We appreciate the comment and the individual comments submitted by the professionals they listed are addressed separately within this ‘Comment’ section.

Full text public comments without protected health information can be viewed at

VIII. CMS Analysis

A. General

When making national coverage determinations, CMS evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member consistent with §1862(a)(1)(A). Critical appraisal of the evidence enables CMS to determine to what degree CMS is confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for beneficiaries. An improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary.

B. Answer to Key Question:

Is the evidence sufficient to conclude that MTWA testing using the MMA method improves health outcomes for Medicare beneficiaries who are candidates for ICD placement?

Our evidence review found 14 unique clinical studies out of 21 relevant publications. There were no randomized controlled trials (RCTs) examining the MMA method, nor any prospectively designed head-to-head studies comparing the MMA and SA methods. Of the 14 studies, ten reported positive results; however, seven of these were conducted outside the U.S. in populations that were generally younger and healthier in terms of number and severity of comorbidities than the Medicare population. One sub-analysis (Nieminen 2014) may have been limited by confounding and two other studies (Stein 2008, Stein 2010) were small, case-control studies with no subsequent confirmatory studies.

There is insufficient evidence to conclude that the two methods of MTWA testing, SA and MMA, are substantially comparable. One study (Exner 2007) included both methods but comparative results were not reported. Thus we cannot confidentially impute results of studies using the SA method to the MMA method.

Other concerns raised in our 2008 NCD were partially addressed. First, study samples generally remain small and it is unclear that they adequately represent the U.S. Medicare population. Several of the publications (Exner 2007; Leino 2009; Leino 2011; Minnikinen 2009; Nieminen 2007; Slawnych 2009) on two of the larger studies (REFINE, FINCAVAS) were conducted outside the U.S The study exclusions combined with sociodemographic differences among countries makes it difficult to generalize these studies to the Medicare population. Generalizability goes to the external validity of clinical trial evidence and is an established criterion for NCDs. The two published studies performed at U.S. centers (Stein 2008; Stein 2010) were small case-control studies. Case-control studies, in general, may help generate hypotheses for further research, but do not establish causality alone. Secondly, there continues to be a lack of adequate control groups generally. Of the eight positive studies, three used matched controls (Nieminen 2014, Stein 2008, Stein 2010). No study was designed to control for the confounding introduced by the selective ICD use or drug therapy (Nieminen 2014).

CMS received 18 public comments on our proposed decision; all commenters were not in favor of national non-coverage. Many of the commenters, which included authors of the published studies that we reviewed for the proposed decision, noted discrepancies in our review of the evidence and analysis. In response, we re-analyzed the specific studies, technology assessments and society position statements. We also included a newly published, supportive systematic review that focused on the MMA method (Quan, Dec 2014). Another review (Verrier and Malik) is in press. Additional research and evidence would be informative. CMS encourages publication of the study results in a peer-reviewed journal which provides an opportunity for open critique. We believe this is an important step in validating the data and results since changes in publications are often made during the peer-review process.

As commenters and authors noted, the MMA method may increase patient access to MTWA technology since no special equipment is required. In addition, the MMA method provides an alternative for patients who are unable to complete an exercise stress test due to medical comorbidities or physical disabilities but have specific compelling reasons to undergo MTWA testing. Based on the new evidence, reanalysis and subsequent reclassification of studies on the MMA method, we find that no national non-coverage determination is appropriate at this time. Although national non-coverage is removed, potential concerns remain with the evidence in the Medicare population, as noted above, so a more favorable national decision is not supported. Reasonable and necessary coverage determinations will be made by the local Medicare contractors who are able to analyze emerging evidence, respond to potential regional variations in access and take into account individual circumstances. CMS will actively monitor and review new evidence as it is published and may reconsider this decision if conditions warrant.

C. Health Disparities

The subjects in key clinical trials evaluating the utility of MTWA testing in patients with left ventricular dysfunction were predominantly male (~75-85%). The proportion of women was higher in studies of advanced heart failure whether ischemic and non-ischemic in origin (~30%) and in studies for other clinical indications (e.g., ~40%in the FINCAVAS series). This finding, in part, reflects the prevalence and earlier onset of coronary heart disease in men.

Racial and ethnic information was not included in the majority of studies. This lack of evidence about racial and ethnic factors is an evidence gap and may be clinically important given the potential for more T-wave alternans aberrancy in non-Caucasians.

None of the clinical trials included demographic information on other population classifiers historically associated with healthcare access or outcome disparities, such as religion, ethnicity, and sexual orientation.

D. Analysis Summary

There were no randomized controlled trials examining the MMA method, nor any prospectively designed head-to-head studies comparing the MMA and SA methods. Several published studies and public commenters supported MMA MTWA. However, generalizability of the published studies to the Medicare population remains a question. Additional studies would help establish the evidence base. We encourage future research, not simply in patients with preserved left ventricular ejection fraction (LVEF), but also in those with depressed LVEF. We are aware that the majority – possibly the vast majority – of patients with depressed LVEF who currently receive ICDs never attain a mortality benefit from them. There is a need for better, evidence-based risk stratification to objectively identify who would likely benefit from an ICD, and who would not.

In summary, CMS is revising its’ decision to allow local contractor discretion based on new evidence, clarifications of published studies that were included in our analysis, public comments, and a reanalysis of the existing supporting evidence.

IX. Conclusion

The Centers for Medicare and Medicaid Services has decided that no National Coverage Determination (NCD) is appropriate at this time for microvolt T-wave alternans (MTWA) testing using the modified moving average (MMA) method for the evaluation of patients at risk for sudden cardiac death (SCD). National non-coverage will be removed. Medicare coverage of MTWA using the MMA method will be determined by the local contractors.



General Methodological Principles of Study Design (Section VI of the Decision Memorandum)

When making national coverage determinations, CMS evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service is reasonable and necessary. The overall objective for the critical appraisal of the evidence is to determine to what degree we are confident that:

1) the specific assessment questions can be answered conclusively; and
2) the intervention will improve health outcomes for patients.

We divide the assessment of clinical evidence into three stages:

1) the quality of the individual studies;
2) the generalizability of findings from individual studies to the Medicare population; and
3) over-arching conclusions that can be drawn from the body of the evidence on the direction and magnitude of the intervention’s potential risks and benefits.

The methodological principles described below represent a broad discussion of the issues we consider when reviewing clinical evidence. However, it should be noted that each coverage determination has its unique methodological aspects.

Assessing Individual Studies

Methodologists have developed criteria to determine weaknesses and strengths of clinical research. Strength of evidence generally refers to: 1) the scientific validity underlying study findings regarding causal relationships between health care interventions and health outcomes; and 2) the reduction of bias. In general, some of the methodological attributes associated with stronger evidence include those listed below:

  • Use of randomization (allocation of patients to either intervention or control group) in order to minimize bias.
  • Use of contemporaneous control groups (rather than historical controls) in order to ensure comparability between the intervention and control groups.
  • Prospective (rather than retrospective) studies to ensure a more thorough and systematical assessment of factors related to outcomes.
  • Larger sample sizes, to demonstrate both statistically significant as well as clinically significant outcomes that can be extrapolated to the Medicare population. Sample size should be large enough to make chance an unlikely explanation for what was found.
  • Masking (blinding) to ensure patients and investigators do not know to that group patients were assigned (intervention or control). This is important especially in subjective outcomes, such as pain or quality of life, where enthusiasm and psychological factors may lead to an improved perceived outcome by either the patient or assessor.

Regardless of whether the design of a study is a randomized controlled trial, a non-randomized controlled trial, a cohort study or a case-control study, the primary criterion for methodological strength or quality is to the extent that differences between intervention and control groups can be attributed to the intervention studied. This is known as internal validity. Various types of bias can undermine internal validity. These include:

  • Different characteristics between patients participating and those theoretically eligible for study but not participating (selection bias).
  • Co-interventions or provision of care apart from the intervention under evaluation (performance bias).
  • Differential assessment of outcome (detection bias).
  • Occurrence and reporting of patients who do not complete the study (attrition bias).

In principle, rankings of research design have been based on the ability of each study design category to minimize these biases. A randomized controlled trial minimizes systematic bias (in theory) by selecting a sample of participants from a particular population and allocating them randomly to the intervention and control groups. Thus, in general, randomized controlled studies have been typically assigned the greatest strength, followed by non-randomized clinical trials and controlled observational studies. The design, conduct and analysis of trials are important factors as well. For example, a well-designed and conducted observational study with a large sample size may provide stronger evidence than a poorly designed and conducted randomized controlled trial with a small sample size. The following is a representative list of study designs (some of that have alternative names) ranked from most to least methodologically rigorous in their potential ability to minimize systematic bias:

  • Randomized controlled trials
  • Non-randomized controlled trials
  • Prospective cohort studies
  • Retrospective case control studies
  • Cross-sectional studies
  • Surveillance studies (e. g., using registries or surveys)
  • Consecutive case series
  • Single case reports

When there are merely associations but not causal relationships between a study’s variables and outcomes, it is important not to draw causal inferences. Confounding refers to independent variables that systematically vary with the causal variable. This distorts measurement of the outcome of interest because its effect size is mixed with the effects of other extraneous factors.

For observational, and in some cases randomized controlled trials, the method in that confounding factors are handled (either through stratification or appropriate statistical modeling) are of particular concern. For example, in order to interpret and generalize conclusions to our population of Medicare patients, it may be necessary for studies to match or stratify their intervention and control groups by patient age or co-morbidities.

Methodological strength is, therefore, a multidimensional concept that relates to the design, implementation and analysis of a clinical study. In addition, thorough documentation of the conduct of the research, particularly study selection criteria, rate of attrition and process for data collection, is essential for CMS to adequately assess and consider the evidence.

Generalizability of Clinical Evidence to the Medicare Population

The applicability of the results of a study to other populations, settings, treatment regimens and outcomes assessed is known as external validity. Even well-designed and well-conducted trials may not supply the evidence needed if the results of a study are not applicable to the Medicare population. Evidence that provides accurate information about a population or setting not well represented in the Medicare program would be considered, but would suffer from limited generalizability.

The extent to that the results of a trial are applicable to other circumstances is often a matter of judgment that depends on specific study characteristics, primarily the patient population studied (age, sex, severity of disease and presence of co-morbidities) and the care setting (primary to tertiary level of care, as well as the experience and specialization of the care provider). Additional relevant variables are treatment regimens (dosage, timing and route of administration), co-interventions or concomitant therapies, and type of outcome and length of follow-up.

The level of care and the experience of the providers in the study are other crucial elements in assessing a study’s external validity. Trial participants in an academic medical center may receive more or different attention than is typically available in non-tertiary settings. For example, an investigator’s lengthy and detailed explanations of the potential benefits of the intervention and/or the use of new equipment provided to the academic center by the study sponsor may raise doubts about the applicability of study findings to community practice.

Given the evidence available in the research literature, some degree of generalization about an intervention’s potential benefits and harms is invariably required in making coverage determinations for the Medicare population. Conditions that assist us in making reasonable generalizations are biologic plausibility, similarities between the populations studied and Medicare patients (age, sex, ethnicity and clinical presentation) and similarities of the intervention studied to those that would be routinely available in community practice.

A study’s selected outcomes are an important consideration in generalizing available clinical evidence to Medicare coverage determinations. One of the goals of our determination process is to assess health outcomes. These outcomes include resultant risks and benefits such as increased or decreased morbidity and mortality. In order to make this determination, it is often necessary to evaluate whether the strength of the evidence is adequate to draw conclusions about the direction and magnitude of each individual outcome relevant to the intervention under study. In addition, it is important that an intervention’s benefits are clinically significant and durable, rather than marginal or short-lived. Generally, an intervention is not reasonable and necessary if its risks outweigh its benefits.

If key health outcomes have not been studied or the direction of clinical effects inconclusive, we may also evaluate the strength and adequacy of indirect evidence linking intermediate or surrogate outcomes to our outcomes of interest.

Assessing the Relative Magnitude of Risks and Benefits

Generally, an intervention is not reasonable and necessary if its risks outweigh its benefits. Health outcomes are one of several considerations in determining whether an item or service is reasonable and necessary. CMS places greater emphasis on health outcomes actually experienced by patients, such as quality of life, functional status, duration of disability, morbidity and mortality, and less emphasis on outcomes that patients do not directly experience, such as intermediate outcomes, surrogate outcomes, and laboratory or radiographic responses. The direction, magnitude, and consistency of the risks and benefits across studies are also important considerations. Based on the analysis of the strength of the evidence, CMS assesses the relative magnitude of an intervention or technology’s benefits and risk of harm to Medicare beneficiaries

Appendix B

20.30 - Microvolt T-Wave Alternans (MTWA)

A. General

Microvolt T-wave Alternans (MTWA) testing is a non-invasive diagnostic test that detects minute electrical activity in a portion of the electrocardiogram (ECG) known as the T-wave. MTWA testing has a role in the stratification of patients who may be at risk for sudden cardiac death (SCD) from ventricular arrhythmias.

Within patient groups that may be considered candidates for implantable cardioverter defibrillator (ICD) therapy, a negative MTWA test may be useful in identifying low-risk patients who are unlikely to benefit from, and who may experience worse outcomes from, ICD placement.

Spectral analysis (SA)is a sensitive mathematical method of measuring and comparing time and the ECG signals. It requires specialized propriety electrodes to calculate minute T-wavevoltage changes. Software then analyzes these microvolt changes and produces a report to be interpreted by a physician. The Modified Moving Average (MMA) method uses a temporal domain in which T-wave alternans are assessed as a continuous variable along the complete ECG. The MMA method of MTWA testing is performed using standard ambulatory ECG equipment.

B. Nationally Covered Indications

Effective for dates of service on and after March 21, 2006, MTWA diagnostic testing is covered for the evaluation of patients at risk for SCD, only when the SA method is used.

C. Nationally Non-Covered Indications


D. Other

Effective for dates of service on and after January 13, 2015, Medicare Administrative Contractors (MACs) acting within their respective jurisdictions may determine coverage of MTWA diagnostic testing for the evaluation of patients at risk for SCD using all other methods.

(This NCD last reviewed January 2015.)


Adam DR, Smith JM, Akselrod S, Nyberg S, Powell AO, Cohen RJ. Fluctuations in T-wave morphology and susceptibility to ventricular fibrillation. J Electrocardiol. 1984;17(3):209-218.

Albert CM, Chae CU, Grodstein F, Rose LM, Rexrode KM, Ruskin JN, Stampfer MJ, Manson JE. Prospective study of sudden cardiac death among women in the United States. Circulation. 2003 Apr 29; 107(16):2096-101.

Arisha MM, Girerd N, Chauveau S, Bresson D, Scridon A, Bonnefoy E, Chevalier P. In-hospital heart rate turbulence and microvolt T-wave alternans abnormalities for prediction of early life-threatening ventricular arrhythmia after acute myocardial infarction. Ann Noninvasive Electrocardiol. 2013 Nov;18(6):530-7. doi: 10.1111/anec.12072. Epub 2013 Oct 23. PMID: 24147791

Byrne R, Constant O, Smyth Y, Callagy G, Nash P, Daly K, Crowley J. Multiple source surveillance incidence and aetiology of out-of-hospital sudden cardiac death in a rural population in the West of Ireland. Eur Heart J. 2008 Jun; 29(11):1418-23.

Chugh SS, Jui J, Gunson K, et al. Current burden of sudden cardiac death: multiple source surveillance versus retrospective death certificate-based review in a large U.S. community. J Am Coll Cardiol. 2004;44:1268–1275.

Cobb LA, Fahrenbruch CE, Olsufka M, Copass MK. Changing incidence of out-of-hospital ventricular fibrillation, 1980–2000. JAMA. 2002;288:3008–3013.

Cox V, Patel M, Kim J, et al. Predicting arrhythmia-free survival using spectral and modified moving average analyses of T-wave alternans. Pacing Clin Electrophysiol. 2007;30:352-358.

de Vreede-Swagemakers JJ, Gorgels AP, Dubois-Arbouw WI, et al. Out-of-hospital cardiac arrest in the 1990's: a population-based study in the Maastricht area on incidence, characteristics and survival. J Am Coll Cardiol. 1997;30:1500-5.

Escobedo LG, Zack MM. Comparison of sudden and nonsudden coronary deaths in the United States. Circulation. 1996;93:2033–2036.

Exner DV, Kavanagh KM, Slawnych MP, Mitchell LB, Ramadan D, Aggarwal SG, Noullett C, Van Schaik A, Mitchell RT, Shibata MA, Gulamhussein S, McMeekin J, Tymchak W, Schnell G, Gillis AM, Sheldon RS, Fick GH, Duff HJ; REFINE Investigators. Noninvasive risk assessment early after a myocardial infarction the REFINE study. J Am Coll Cardiol. 2007 Dec 11;50(24):2275-84. Epub 2007 Nov 26. PMID: 18068035

Fishman GI, Chugh SS, DiMarco JP, et al. Sudden cardiac death prediction and prevention: report from a National Heart, Lung, and Blood Institute and Heart Rhythm Society workshop. Circulation. 2010;122:2335–48.

Fox CS, Evans JC, Larson MG, Kannel WB, Levy D. Temporal trends in coronary heart disease mortality and sudden cardiac death from 1950–1999: the Framingham Heart Study. Circulation. 2004;110:522–527.

Gillum RF. Sudden coronary death in the United States: 1980–1985. Circulation. 1989;79:756–765.

Hohnloser SH, Ikeda T, Cohen RJ. Evidence regarding clinical use of microvolt T-wave alternans. Heart Rhythm. 2009;6:S36-44.

Hoshida K, Miwa Y, Miyakoshi M, Tsukada T, Yusu S, Yoshino H, Ikeda T. Simultaneous assessment of T-wave alternans and heart rate turbulence on holter electrocardiograms as predictors for serious cardiac events in patients after myocardial infarction. Circ J. 2013;77(2):432-8. Epub 2012 Oct 12. PMID: 23059771

Huikuri H, Castellanos A, Myerburg RJ. Sudden death due to cardiac arrhythmias. N Engl J Med. 2001;345:1473–1482.

Junttila MJ, Barthel P, Myerburg RJ, Ma¨kikallio TH, Bauer A, Ulm K,Kiviniemi A, Tulppo M. Perkio¨ma¨ki JS, Schmidt G, Huikuri HV. Sudden cardiac death after myocardial infarction in patients with type 2 diabetes.Heart Rhythm. 2010;7:1396 –1403.

Kenttä T, Tulppo MP, Nearing BD, Karjalainen JJ, Hautala AJ, Kiviniemi AM, Huikuri HV, Verrier RL. Effects of exercise rehabilitation on cardiac electrical instability assessed by T-wave alternans during ambulatory electrocardiogram monitoring in coronary artery disease patients without and with diabetes mellitus. Am J Cardiol. 2014 Sep 15;114(6):832-7. doi: 10.1016/j.amjcard.2014.06.014. Epub 2014 Jul 2. PMID: 25107578

Kim R, Cingolani O, Wittstein I, McLean R, Han L, Cheng K, Robinson E, Brinker J, Schulman SS, Berger RD, Henrikson CA, Tereshchenko LG. Mechanical alternans is associated with mortality in acute hospitalized heart failure: prospective mechanical alternans study (MAS). Circ Arrhythm Electrophysiol. 2014 Apr;7(2):259-66. doi: 10.1161/CIRCEP.113.000958. Epub 2014 Mar 1. PMID: 24585716

Kong MH, Fonarow GC, Peterson ED, Curtis AB, Hernandez AF, Sanders GD, Thomas KL, Hayes DL, Al-Khatib SM. Systematic review of the incidence of sudden cardiac death in the United States. J Am Coll Cardiol. 2011;57:794–801.

Leino J, Minkkinen M, Nieminen T, Lehtimäki T, Viik J, Lehtinen R, Nikus K, Kööbi T, Turjanmaa V, Verrier RL, Kähönen M. Combined assessment of heart rate recovery and T-wave alternans during routine exercise testing improves prediction of total and cardiovascular mortality: the Finnish Cardiovascular Study. Heart Rhythm. 2009 Dec;6(12):1765-71. doi: 10.1016/j.hrthm.2009.08.015. Epub 2009 Aug 14. PMID: 19959127

Leino J, Verrier RL, Minkkinen M, Lehtimäki T, Viik J, Lehtinen R, Nikus K, Kööbi T, Turjanmaa V, Kähönen M, Nieminen T. Importance of regional specificity of T-wave alternans in assessing risk for cardiovascular mortality and sudden cardiac death during routine exercise testing. Heart Rhythm. 2011 Mar;8(3):385-90. doi: 10.1016/j.hrthm.2010.11.004. Epub 2010 Nov 5. PMID: 21056698

Li-na R, Xin-hui F, Li-dong R, Jian G, Yong-quan W, Guo-xian Q. Ambulatory ECG-based T-wave alternans and heart rate turbulence can predict cardiac mortality in patients with myocardial infarction with or without diabetes mellitus. Cardiovasc Diabetol. 2012 Sep 6;11:104. PMID: 22950360

Lloyd-Jones D, Adams RJ, Brown TM, et al. J. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2010 update: a report from the American Heart Association. Circulation. 2010;121:e46–e215.

Marrugat J, Elousa R, Gil M. Epidemiología de la muerte súbita cardíaca en España. Rev Esp Cardiol. 1999;52:717-25.

Martinez JP, Olmos S. Methodological principles of T wave alternans analysis: a unified framework. IEEE Trans Biomed Eng 2005; 52:599–613.

Masiá R, Pena A, Marrugat J, et al. High prevalence of cardiovascular risk factors in Gerona, Spain, a province with low myocardial infarction incidence. REGICOR Investigators. J Epidemiol Community Health. 1998;52:707-15.

Minkkinen M, Kähönen M, Viik J, Nikus K, Lehtimäki T, Lehtinen R, Kööbi T, Turjanmaa V, Kaiser W, Verrier RL, Nieminen T. Enhanced predictive power of quantitative TWA during routine exercise testing in the Finnish Cardiovascular Study. J Cardiovasc Electrophysiol. 2009 Apr;20(4):408-15. doi: 10.1111/j.1540-8167.2008.01325.x. Epub 2008 Oct 11. PMID: 1917584

Myerburg RJ. Sudden cardiac death: exploring the limits of our knowledge. J Cardiovasc Electrophysiol. 2001;12:369–381.

Myerburg RJ, Kessler KM, Castellanos A. Sudden cardiac death: structure, function and time-dependent risk. Circulation. 1992:85(suppl 1):1–10.

Myerburg RJ, Kessler KM, Castellanous A. Epidemiology of sudden cardiac death: Population characteristics, conditioning risk factors, and dynamic risk factors. Ion Channels in the Cardiovascular System: Function and Dysfunction. 1994:15–35.

National Institutes of Health (NIH) Workshop. Prediction and Prevention of Sudden Cardiac Death. 2009.

Nichol G, Thomas E, Callaway CW, Hedges J, Powell JL, Aufderheide TP, Rea T, Lowe R, Brown T, Dreyer J, Davis D, Idris A, Stiell I. Regional variation in out-of-hospital cardiac arrest incidence and outcome. JAMA. 2008;300:1423–1431.

Nieminen T, Lehtinen R, Viik J, Lehtimäki T, Niemelä K, Nikus K, Niemi M, Kallio J, Kööbi T, Turjanmaa V, Kähönen M. The Finnish Cardiovascular Study (FINCAVAS): characterising patients with high risk of cardiovascular morbidity and mortality. BMC Cardiovasc Disord. 2006 Mar 3;6:9. PMID: 16515696

Nieminen T, Lehtimaki T, Viik J, et al. T-wave alternans predicts mortality in a population undergoing a clinically indicated exercise test. Eur Heart J. 2007;28:2332-2337.

Nieminen T, Scirica BM, Pegler JRM, et al. Relation of T-wave alternans to mortality and nonsustained ventricular tachycardia in patients with non-ST segment elevation acute coronary syndrome from the MERLIN-TIMI 36 trial of ranolazine versus placebo. Am J Cardiol. 2014; 114:17-23.

Quan X, Zhou H, Ruan L, Lv J, Yao J, Yao F, Huang K, Zhang C. Ability of ambulatory ECG-based T-wave alternans to modify risk assessment of cardiac events: a systematic review BMC Cardiovasc Disord. 2014 Dec 20;14(1):198. [Epub ahead of print] PMID: 25528490

Ren L-N, Fang X, Wang Y, Qi G. T-wave alternans and heart rate variability: a comparison in patients with myocardial infarction with or without diabetes mellitus. Ann Noninvasive Electrocardiol. 2011 Jul;16(3):232-8. doi: 10.1111/j.1542-474X.2011.00437.x. PMID: 21762250

Roger VL, Go AS, Lloyd-Jones DM, et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2011 update: a report from the American Heart Association. Circulation. 2011;123:e18–e209.

Sakaki K, Ikeda T, Miwa Y, Miyakoshi M, Abe A, Tsukada T, Ishiguro H, Mera H, Yusu S, Yoshino H. Time-domain T-wave alternans measured from Holter electrocardiograms predicts cardiac mortality in patients with left ventricular dysfunction: a prospective study. Heart Rhythm. 2009 Mar;6(3):332-7. doi: 10.1016/j.hrthm.2008.12.011. Epub 2008 Dec 7. PMID: 19251207

Schwartz PJ, Malliani A. Electrical alternation of the T-wave: clinical and experimental evidence of its relationship with the sympathetic nervous system and with the long Q-T syndrome. Am Heart J. 1975;89:45–50.

Slawnych MP, Nieminen T, Kähönen M, Kavanagh KM, Lehtimäki T, Ramadan D, Viik J, Aggarwal SG, Lehtinen R, Ellis L, Nikus K, Exner DV; REFINE (Risk Estimation Following Infarction Noninvasive Evaluation); FINCAVAS (Finnish Cardiovascular Study) Investigators. Post-exercise assessment of cardiac repolarization alternans in patients with coronary artery disease using the modified moving average method. J Am Coll Cardiol. 2009 Mar 31;53(13):1130-7. doi: 10.1016/j.jacc.2008.12.026. PMID: 19324258

Stein PK, Sanghavi D, Domitrovich PP, Mackey RA, Deedwania P. Ambulatory ECG-based T-wave alternans predicts sudden cardiac death in high-risk post-MI patients with left ventricular dysfunction in the EPHESUS study. J Cardiovasc Electrophysiol. 2008 Oct;19(10):1037-42. doi: 10.1111/j.1540-8167.2008.01225.x. Epub 2008 Jun 28. PMID: 18554193

Stein PK, Sanghavi D, Sotoodehnia N, Siscovick DS, Gottdiener J. Association of Holter-based measures including T-wave alternans with risk of sudden cardiac death in the community-dwelling elderly: the Cardiovascular Health Study. J Electrocardiol. 2010 May-Jun;43(3):251-9. doi: 10.1016/j.jelectrocard.2009.12.009. Epub 2010 Jan 25. PMID: 20096853

Subirana MT, Juan-Babot JO, Puig T, et al. Specific characteristics of sudden death in Mediterranean area. Am J Cardiol. 2011;107:622-7.

Sulimov V, Okisheva E, Tsaregorodtsev D. Non-invasive risk stratification for sudden cardiac death by heart rate turbulence and microvolt T-wave alternans in patients after myocardial infarction. Europace. 2012 Dec;14(12):1786-92. doi: 10.1093/europace/eus238. Epub 2012 Jul 31. PMID: 22849973

Surgit O, Erturk M, Akgul O, Pusuroglu H, Korkmaz AF, Avci Y, Ozal E, Uzun F, Buturak A, Eksik A. Assessment of the relationship between nondipping phenomenon and microvolt T-wave alternans. Blood Press Monit. 2014 Aug 13. [Epub ahead of print] PMID: 25121754

Surgit O, Erturk M, Buturak A, Akgul O, Pusuroglu H, Cakmak HA, Yazan S, Gul M, Akkaya E, Eksik A. The assessment of relationship between left ventricular geometry and microvolt T-wave alternans in sustained hypertension. Blood Press. 2014 Jun 12:1-7. [Epub ahead of print] PMID: 24919782

Trojnarska O, Ciepłucha A, Bartczak A, Kramer L, Grajek S. Microvolt T-wave alternans in adults with complex congenital heart diseases. Cardiol J. 2014;21(2):144-51. doi: 10.5603/CJ.a2013.0124. Epub 2013 Oct 21. PMID: 24142674

Vaillancourt C, Stiell IG, Canadian Cardiovascular Outcomes Research Team. Cardiac arrest care and emergency medical services in Canada. Can J Cardiol. 2004; 20(11): 1081-1090.

Verrier R. Klingenheben T, Malik M, et al. Microvolt t-wave alternans: physiological basis, methods of measurement, and clinical utility: consensus guideline by International Society for Holter and Noninvasive Electrocardiology. J Am Coll Cardiol. 2011;58:1309-1324.

Verrier RL, Malik M. Quantitative T-wave alternans analysis for guiding medical therapy: an underexploited opportunity. Trends in Cardiovascular Medicine, in press.

Yu H, Pi-Hua F, Yuan W, et al. Prediction of sudden cardiac death in patients after acute myocardial infarction using T-wave alternans: a prospective study. J Electrocardiol. 2012;45:60-65.