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Decision Memo for
Microvolt T-wave Alternans (CAG-00293N) |
CMS has determined that there is
sufficient evidence to conclude that Microvolt T-wave Alternans (MTWA)
diagnostic testing is reasonable and necessary for the evaluation of patients
at risk of sudden cardiac death, only when the spectral analytic method is
used, and CMS is issuing the following national coverage determination (NCD)
for this indication.
Microvolt
T-wave Alternans (MTWA) diagnostic testing is covered for the evaluation of
patients at risk of sudden cardiac death, only when the spectral analytic
method is used.
TO: |
Administrative File: CAG #00293 |
FROM: |
Steve E. Phurrough, MD, MPA Louis Jacques, MD Stuart Caplan, RN, MAS Jim Rollins, MD, MSHA, PhD |
SUBJECT: |
Decision Memorandum for Microvolt T-wave Alternans
Testing |
DATE: |
March 21, 2006 |
I. Decision
CMS has determined that there is
sufficient evidence to conclude that Microvolt T-wave Alternans (MTWA)
diagnostic testing is reasonable and necessary for the evaluation of patients
at risk of sudden cardiac death, only when the spectral analytic method is
used, and CMS is issuing the following national coverage determination (NCD)
for this indication.
Microvolt
T-wave Alternans (MTWA) diagnostic testing is covered for the evaluation of
patients at risk of sudden cardiac death, only when the spectral analytic
method is used.
II. Background
Cardiovascular disease is the
single most common cause of death in the United States. Sudden cardiac death
(SCD) is estimated to account for approximately 50% of all cardiovascular
deaths. This represents an estimated 350,000 cases per year and only about 20%
of these patients survive to hospital discharge. Ventricular tachyarrhythmic
events (VTE) are the mechanism responsible for 75-80% of these deaths
(Huikuri, 2001).
Microvolt T-wave Alternans
(MTWA) testing is a non-invasive diagnostic test that detects minute
electrical activity in a portion of the electrocardiogram (EKG) know as the
T-wave. Published articles in medical journals have proposed that MTWA testing
has a role in the risk 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, published literature indicates that 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.
The test is performed by placing
high-resolution electrodes, designed to reduce electrical interference, on a
patient’s chest prior to a period of controlled exercise. These electrodes
detect tiny beat-to-beat changes, on the order of one-millionth of volt, in
the EKG T-wave. Spectral analysis is used to calculate these minute voltage
changes. Spectral analysis is a sensitive mathematical method of measuring and
comparing time and the electrocardiogram signals. Software then analyzes these
microvolt changes and produces a report to be interpreted by a physician.
In a January 27, 2005 final
decision memorandum for ICDs, CMS stated:
“We
do strongly encourage the inclusion of MTWA is subsequent clinical trials,
registries and other data collection protocols in order to further evaluate
this promising risk-stratification technology and will work with the
stakeholders involved in the subsequent data collection systems to include
this information. CMS will continue to support these studies that collect this
type of information.”
III. History of Medicare
Coverage
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) §
1861(s) (Definition of Medical and Other Health Services). MTWA may be
eligible for coverage under the Social Security Act section 1861(s)(3) “other
diagnostic tests”.
CMS does not currently have an
NCD on MTWA testing. Coverage is at local Medicare contractor discretion.
IV. Timeline of Recent
Activities
July 5, 2005 July 7, 2005 |
CMS meets with the requestor,
Cambridge Heart. CMS opens an NCD to evaluate
the use of MTWA testing in the Medicare population. CMS begins a national
coverage determination review in response to an external request. A 30-day
public comment period is opened. |
August 5, 2005 |
Public comment period closes. CMS
completes the posting of public comments to the coverage website. |
December 21, 2005 |
Draft decision memorandum
posted. A second 30-day public comment period is opened. |
February 21, 2006 |
Second public comment period
closes. CMS completes the posting of these public comments to the coverage
website. |
V. FDA Status
The Food and Drug Administration
(FDA) has cleared Heartwave™ alternans devices, along with various software
packages used to perform MTWA testing, through the 510(k) clearance process.
Clearance was obtained on July 16, 2002 (K022152) and November 17, 2002
(K03564).
VI. General Methodological Principles
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. The critical appraisal of the evidence enables us
to determine to what degree we are confident that: 1) the specific assessment
questions can be answered conclusively; and 2) the intervention will improve
net health outcomes for patients. Improved net health outcomes are one of
several considerations in determining whether an item or service is reasonable
and necessary. In general, features of clinical studies that improve quality
and decrease bias include the selection of a clinically relevant cohort, the
consistent use of a single good reference standard, and the blinding of
readers of the index test, and reference test results.
A detailed account of the
methodological principles of study design that agency staff utilizes to assess
the relevant literature on a therapeutic or diagnostic item or service for
specific conditions can be found in Appendix B. In general, features of
clinical studies that improve quality and decrease bias include the selection
of a clinically relevant cohort, the consistent use of a single good reference
standard, and the blinding of readers of the index test, and reference test
results.
Public comment sometimes cites
the published clinical evidence and gives CMS useful information. Public
comments that give information on unpublished evidence such as the results of
individual practitioners or patients are less rigorous and therefore less
useful for making a coverage determination. CMS uses the initial public
comments to inform its proposed decision. CMS responds in detail to the public
comments on a proposed decision when issuing the final decision memorandum.
VII. Evidence
A. Introduction
We are providing a summary of
the evidence we considered during our review. The evidence reviewed to date in
this decision memorandum includes the published medical literature on
pertinent clinical trials of MTWA.
B. Discussion of
Evidence Reviewed
1. Questions
1. Is the quality of evidence
adequate to conclude that MTWA testing can improve net health outcomes and is
reasonable and necessary for Medicare patients who are candidates for ICD
placement?
2. If the evidence is
adequate to conclude that MTWA testing can improve net health outcomes, what
characteristics of the test method, the pathologic condition, or the patient
can satisfactorily predict an improved health outcome?
2. External technology assessments
We did not request an external
technology assessment (TA) on this issue. CMS reviewed a TA published in
October 2005 by the National Blue Cross and Blue Shield Association’s
Technology Evaluation Center (BCBSA TEC) entitled “Microvolt T-wave alternans
testing to risk stratify patients being considered for ICD therapy for primary
prevention of sudden death”. That assessment concluded that MTWA did not meet
BCBSA TEC criteria for coverage. The committee felt that the evidence was
insufficient to permit conclusions regarding the effect on health outcomes,
the evidence was insufficient to determine whether the use of MTWA improved
net health outcomes or whether it is as beneficial as any established
alternatives, and the use of MTWA to improve outcomes in the investigational
setting had not been established.
3. Internal technology assessments
Literature search methods
The reviewed evidence was gathered
from: 1) articles submitted by the requestor; 2) an existing technology
assessment, and 3) a literature search of the PubMed database.
To support their request for
coverage, the requestor submitted a listing of 1028 citations on a compact
disc entitled “Publications and Abstracts: Clinical Compendium”. These
citations included articles on technical feasibility, mathematical models,
animal studies, pediatric populations, pharmacologic interventions, and
applications of MTWA for other than the requested indication (e.g.,
hypertension, cardiac pacing). Along with the list of 1028 citations was a
separate “Table of Contents” of recent publications relevant to the coverage
request. From this list, CMS excluded poster presentations, oral
presentations, editorials, review articles, studies that did not specifically
address MTWA as a risk stratifier for patients eligible for ICD treatment, and
those lacking sufficiently detailed information on study design or discussion
of results. From this “Table of Contents”, and following a discussion with the
requestor, 12 of the submitted articles were considered for review.
Bibliographies of these publications were reviewed to identify additional
relevant articles.
The limits of our PubMed search
excluded non-English articles, studies with fewer than 10 cases, and those not
involving human subjects. The search terms used were:
§
T-wave alternans, arrhythmia
§
T-wave alternans, ventricular
§
T-wave alternans, implantable cardioverter
defibrillator (ICD)
§
T-wave alternans, cardiac defibrillator (ICD)
§
T-wave alternans, (MADIT) II
§
T-wave alternans, sudden cardiac death
§
T-wave alternans, ejection
§
T-wave alternans, infarction
§
T-wave alternans, cardiomyopathy
§
T-wave alternans, primary prevention
From the initial PubMed yield,
CMS then applied the same exclusion criteria described above. Using these
terms and exceptions, CMS did not identify any additional articles to those
supplied by the requestor.
Evidence Review
A number of studies evaluating
the effectiveness of MWTA have been found in the medical literature. These
include studies evaluating MWTA in patients with ischemic cardiomyopathies,
non-ischemic dilated cardiomyopathies, as well as in patients with mixed
cardiomyopathies. Endpoints studied include morbidity, mortality (e.g., sudden
cardiac deaths, VTE, as well as quality of life measures. Evaluations ranged
from single prospective studies to systematic reviews (meta-analysis and
article reviews).
Gehi and associates recently
performed a meta-analysis evaluating the use of MTWA in determining risk
stratification of VTE across a wide range of patient populations (Gehi, Stein,
Metz, Gomes, 2005). Using PubMed and Cochrane databases to identify published
articles performed between January 1990 and December 2004, 19 prospective
studies, which included 2,608 subjects, were found which met the following
inclusion criteria: 1) prospective cohort studies of greater than 10 subjects
who underwent exercise induced MTWA testing for the prediction of SCD or
ventricular arrhythmias; 2) provided primary data on results of MTWA and of
clinical outcomes including SCD, cardiac death, ventricular arrhythmias,
and/or implantable cardioverter defibrillator (ICD) shock; 3) provided clear
definition of normal or abnormal MTWA testing; and 4) had a follow-up time of
six months or longer. Outcomes of each study were presented as Positive
Predictive Value (PPV), Negative Predictive Value (NPV), and univariate
Relative Risk (RR) with Confidence Intervals (CIs) of MTWA for the prediction
of ventricular arrhythmic events at follow up.
Study sample sizes ranged from
16 to 834 participants. The mean age of the subjects in the 19 studies ranged
from 25 to 64 years, and the average follow-up was 21 months. There was a wide
range of subject populations including congestive heart failure (CHF),
ischemic CHF, non-ischemic CHF, post myocardial infarction (MI), athletes, and
healthy subjects. Mean ejection fraction (EF) of study participants ranged
from 23 to 71. After excluding all subjects with indeterminate MTWA test, the
PPV at follow-up ranged from 0% to 67%, while the NPV ranged from 71 to 100%.
The RR for having a cardiac event ranged from 0.85 to infinity.
For the 19 studies the summary
PPV during the 21 months of follow-up was 19.3% (95% CI 17.7% to 21%); the NPV
was 97.2% (95% CI 95.5% to 97.9%), and the univariate RR was 3.77 (95% CI 2.39
to 5.95). The study found that the presence of significant MTWA predicted
nearly a four-fold risk of VTE compared to the absence of significant MTWA.
The absence of MTWA carries a 3% risk of arrhythmic events during an average
21 months of follow-up. The study also revealed that there was no significant
difference in PPV, NPV, or RR of MTWA testing between subjects with ischemic
and non-ischemic CHF, as well as no significant difference in the NPV or RR of
MTWA testing between CHF and post-MI subjects.
Three studies performed a
multivariate Cox regression analysis to determine the independent predictive
value of commonly used tests for risk stratification of arrhythmic events. In
these three studies, MTWA was independently predictive of arrhythmic events.
In Gehi’s assessment of all the
articles included in the analysis, none of the studies were of poor quality,
testing revealed appropriate heterogeneity, and no evidence of publication
bias was found. In this review MTWA was absent in 25% to 54% of subjects,
which the author felt was a significant portion of subjects.
Gehi noted that there were some
limitations of this meta-analysis including, insufficient data in the multivariate
analysis to determine the incremental prognostic value of MWTA independent of
other predictors of arrhythmic events, the endpoints of the individual studies
used in the summary calculations were variable, most of the subjects included
in these studies were primarily men (making the results difficult to
generalize to females), and the inconsistency in the exclusion of subjects
using beta-blockers or anti-arrhythmic medications.
One of the first clinical
studies that was able to demonstrate that electrical alternans was a marker
for vulnerability for ventricular arrhythmias was performed by Rosenbaum and
associates (Rosenbaum, Jackson, Smith, Garan, Ruskin, Cohen, 1994). The study
consisted of 83 consecutive patients who were sent for diagnostic electrophysiologic
studies and who met entry criteria (excluded if atrial pacing was not
possible; if a permanent pacemaker had been previously implanted; or if
excessive ventricular ectopic beats were present). Baseline measurements of
electrical alternans were compared with the results of baseline
electrophysiologic testing in each patient, along with the relation of
electrical alternans to arrhythmia-free survival. Of the 83 patients that
entered the study, 17 were excluded from the survival analysis because
anti-arrhythmic drug therapy was initiated or changed during the follow-up
period.
Of the 66 patients followed for
up to 20 months, 13 had arrhythmic events (5 of the events were SCD, the
remainders were ventricular arrhythmias). The level of T-wave alternans was
significantly greater in patients who had arrhythmic events than in patients
without events. This study also revealed that two independent predictors of
inducible ventricular arrhythmias were repolarization alternans (ST-segment or
T-wave alternans), and impaired left ventricular function. Further studies
using multivariate analysis showed that repolarization alternans identified
underlying electrical instability, independent of structural heart disease.
Subsequent studies have
confirmed the role of T-wave alternans as a predictor for VTEs. Gold and
associates compared T-wave alternans, signal-averaged electrocardiography
(SAE), and programmed ventricular stimulation for arrhythmia risk
stratification in patients undergoing electrophysiologic studies (Gold,
Bloomfield, Anderson, El-Sherif, Wilber, et al. 2000). This study was
initiated because the authors felt that accurate identification of patients at
increased risk for sustained ventricular arrhythmias was critical to prevent
sudden cardiac death. They felt that T-wave alternans correlated with
arrhythmia vulnerability, but at that point in time, SAE and programmed
ventricular stimulation were more commonly used for risk stratification of
this condition. This prospective, multicenter study consisted of 313
participants who underwent diagnostic electrophysiologic studies for T-wave
alternans testing using a spectral analysis algorithm. Programmed ventricular
stimulation as well as signal averaged electrocardiography were also
performed. The primary endpoint was the occurrence of a VTE, while secondary
endpoints included a VTE or all-cause mortality. Based on the Kaplan Meier
survival analysis as the primary endpoint, MTWA predicted events with a RR of
10.9 compared to RR of 7.1 and 4.5 as predicted by programmed ventricular
stimulation, and SAE respectively. The RR for secondary endpoints were 13.9,
4.7 and 3.3 respectively also. When comparing statistical performance of the
noninvasive test to predict the results of programmed ventricular stimulation
during electrophysiological testing, MTWA and SAE resulted in the following:
|
Sensitivity |
Specificity |
PPV |
NPV |
RR |
p-value |
MTWA |
77.8% |
72.5% |
42.9% |
92.5% |
5.7 |
<0.0001 |
SAE |
55.6% |
83.3% |
46.9% |
87.5% |
3.8 |
<0.0001 |
To assess the independent
predictors of clinical events, a multivariate analysis was performed based on
11 of the clinical parameters. MTWA was identified as the only independent
predictor of cardiac events. Compared to SAE, MTWA was a more sensitive predictor
of the induction of a sustained VT during programmed ventricular stimulation,
as well as a better discriminator of VTEs or death.
Hohnloser and colleagues also
evaluated MTWA’s usefulness in predicting VTEs in patients with dilated
cardiomyopathies (Hohnloser, Klingenheben, Bloomfield, Dabbous, Cohen, 2003).
This study used consecutive patients referred to a heart failure clinic for
management of their condition, or to the electrophysiologic laboratory for
evaluation of symptomatic arrhythmias. Inclusion criteria for the study
included a diagnosis of dilated cardiomyopathy, no intercurrent illnesses
limiting life expectancy, and the presence of sinus rhythm at initial
presentation. Risk stratification was performed at entry, and assessment
included determination of left ventricular ejection fraction (LVEF), heart
rate variability, mean 24-hour RR interval, presence of non-sustained VT
(NSVT), baroreflex sensitivity (BRS), and analysis of signal-averaged
electrocardiography (SAE). Patients at high risk were defined by: LVEF <35%;
mean RR <700 ms; HR variability; standard deviation of
normal-to-normal intervals <70 ms (SDNN); and BRS <3.0
ms/mm Hg. An intraventricular conduction defect (IVCD) was defined as a QRS
duration of > 120 ms. Endpoints included sudden cardiac death (SCD),
cardiac arrest due to VF, hemodynamically unstable VT or VF.
A total of 137 patients with
non-ischemic dilated cardiomyopathy were included in the study (31 females,
and 106 males with a mean age of 55). At study entry 37 patients (27%) had
been fitted with an ICD because of prior history of cardiac arrest, documented
sustained VT, syncope, or for prophylactic reasons. Patients were followed for
18 months. MTWA, using a spectral analysis algorithm, was positive in 66
patients (48%), negative in 34 patients (25%), and indeterminate in 37 (27%).
A multivariate analysis was performed looking at the outcomes of the various
risks stratification methods. Results of the analysis revealed that MTWA was
the only independent statistical predictor of arrhythmic events (X2 of 3.87). In patients with ICDs versus
those without ICDs, the number of persons with positive MTWA test was 23 (62%)
versus 43 (43%), and the number with a negative MTWA test results was 5 (14%)
versus 29 (29%) (both numbers were statistically significant), and the number
with indeterminate test was 9 (24%) versus 28 (28%) which was not
statistically significant. The author concluded that the study demonstrated
that MTWA positive patients are at particularly high risk for VTEs.
Limitations of the study noted by the authors included a high number of
patients enrolled in the study after receiving an ICD, and only including
hemodynamically unstable VTEs as endpoints in these ICD recipients.
|
Sensitivity |
Specificity |
PPV |
NPV |
RR |
p-value |
MTWA |
87% |
37% |
22% |
94% |
3.4 |
<0.0001 |
SAE |
47% |
63% |
17% |
88% |
1.4 |
<0.0001 |
LVEF< 35% |
80% |
21% |
15% |
86% |
1.0 |
|
A number of other studies have
evaluated the use of MTWA in patients with dilated cardiomyopathies. Kitamura
and colleagues prospectively followed 104 patients with dilated cardiomyopathy
(mean age 52 years) to determine the prognostic value of onset heart rate
(OHR) in MTWA (using a spectral analysis algorithm) in patients with
non-ischemic dilated cardiomyopathy (Kitamura, Ohnishi, Okajima, Ishida et al.
2002). All patients were in sinus rhythm and dilated cardiomyopathy was
clinically diagnosed according to the criteria recommended by the World Health
Organization and the National Heart, Lung, and Blood Institute. To define the
high risk subgroup, MTWA positive patients were categorized according to a
predetermined cut-off point of OHR for MTWA of <100 beats/min which
represented the division between the two groups (group A consisted of patients
with OHR <100 beats/min and group B with 100 < OHR <110).
MTWA negative patients were designated group C. Conventional markers including
left ventricular end-diastolic diameter (LVDd) left ventricular ejection
fraction (LVEF), non-sustained ventricular tachycardia (NSVT), SAE were used
for comparison purposes. Endpoints included sudden cardiac death (SCD), or
documented SVT/VF. Forty-six of the patients (44%) were MTWA positive, while
37 (36%) were MTWA negative. The remainder 21 (20%) were MTWA indeterminate.
After excluding patients for poor electrocardiogram recordings, only 83
patients remained in the study. Of the 46 MTWA positive patients, 24 were
categorized in group A, while 22 were in group B. Both groups were comparable
in terms of heart rate, and the OHR of MTWA was not significantly correlated
with LVEF (r=0.025). There were 9 cardiac events in group A, and 2 cardiac
events in group B. Only 1 cardiac event occurred in group C. Further analysis
revealed that the determination of OHR in combination with MTWA could identify
the high risk subgroup among the 83 patients with dilated cardiomyopathy.
Using multivariate Cox hazard analysis, the study revealed that MTWA with OHR <100
beats/min and left LVEF were the only independent predictors of arrhythmic
events.
|
Sensitivity |
Specificity |
PPV |
NPV |
RR |
MTWA |
91.7% |
50.7% |
23.9% |
97.3% |
8.8 |
SAE |
41.7% |
78.9% |
25% |
88.9% |
2.3 |
LVEF< 35% |
66.7% |
66.2% |
25% |
92.2% |
3.2 |
Adachi and associates also
studied the use of MTWA as a risk stratification tool in patients with dilated
cardiomyopathy (Adachi, Ohnishi, Yokoyama 2001). This study consisted of 82
consecutive patients with a diagnosis of non-ischemic dilated cardiomyopathy
that were referred for electrophysiologic studies. MTWA testing was performed,
as well as left ventricular end-diameter (LVDd), left ventricular ejection
fraction (LVEF), signal-average ECG (SAECG), 24 hour Holter monitoring for
non-sustained VT (NSVT), as well as QT dispersion (QTd) for comparison
purposes. Endpoints included sudden cardiac death (SCD), documented SVT, or
resuscitated VF. The follow-up period lasted for 24 months. In this study, 37%
of participants were MTWA positive, 41% were MTWA negative, and the remaining
22% were indeterminate. The percentage of patients with MTWA in the arrhythmic
events group (group A) was significantly larger than that in the non-event
group (group B) (90% versus 39%). When evaluating MTWA and other predictor markers
for event-free survival, the following matrix is created:
|
Sensitivity |
Specificity |
PPV |
NPV |
RR |
p-values |
MTWA |
90% |
61% |
30% |
97% |
10.2 |
0.0029 |
SAE |
40% |
80% |
27% |
88% |
2.2 |
0.1783 |
LVEF< 35% |
70% |
80% |
39% |
93% |
6.0 |
0.0013 |
A multivariate Cox regression
analysis revealed that a combination of an LVEF of <35% along with
MTWA positivity were the only statistically significant independent risk
factors for VTEs. None of the patients who were MTWA negative and who had an
LVEF>35% experienced arrhythmic events. The author did note that small
sample size, as well as the exclusion of patients from the study due to atrial
fibrillation, were some limitations of this study.
Momiyama and associates evaluated
MTWA using a spectral analysis algorithm as a marker of high risk in patients
with hypertrophic cardiomyopathy (HCM), comparing 14 patients with HCM to 9
normal controls (Momiyama, Hartikainen, Nagayoshi, Albrecht et al. 1997). Risk
stratification for VTEs had been made prior to the study based on an adverse
family history, the detection of VT on ambulatory electrocardiogram
monitoring, and the finding of paced ventricular electrograms. Of the 14
patients with HCM, 7 were classified as high risk for VTEs, while the other 7
were determined to be of low risk. Nine healthy volunteers made up the control
group. There were no significant differences in age or gender in the 3 groups.
MTWA voltage was used as a measure (defined as >1.9µV during a period of >250
betas with a HR >100 beats/min), while VTEs, and sudden cardiac death (SCD)
were chosen as endpoints. The results of the alternans analysis revealed that
the alternans voltage was significantly higher in the high-risk group than in
the low-risk and control groups (2.8+/-1.7 vs 0.6+/-0.5). In the high-risk
group, the median alternans ratio was also significantly greater than in the
low-risk group as well as the control group (3.9 vs 0.6 and 0.3). Of the 7
high-risk participants, 5 (71%) showed significant MTWA voltage (3.7+/-1.0),
whereas none of the 7 low-risk patients or the 9 control subjects had MTWA
1.9µV. Of particular note, the study documented that all 4 patients with
sustained VT or abnormal paced ventricular electrograms exhibited MTWA. Limitations
of the study included small sample size, the inability to elucidate the
quantitative relationship between MTWA, and the inhomogeneity of
intramyocardial conduction assessed by electrophysiologic testing because it
was performed in only 6 of 14 patients.
A number of studies have
evaluated the usefulness of MTWA as a predictor of cardiac events after a
myocardial infarction (MI). Ikeda and associates used a combined assessment of
MTWA and other predictive test to predict arrhythmias after myocardial infarction
(Ikeda, Sakata, Takami, Kondo et al. 2000), and later with other collaborators
Ikeda used MTWA as a predictor for sudden cardiac death after myocardial
infarction (Ikeda, Saito, Tanno, Shimizu, 2000). In the first study, 102
consecutive patients with an acute MI were followed longitudinally, comparing
MTWA, late potentials (LP) by SAE, and ejection fractions (EF) for the
detection of arrhythmic events (LP as determined by SAE, and left ventricular
ejection fraction have been used to identify patients at risk for the
development of ventricular arrhythmias). Documentation of spontaneous
ventricular arrhythmic events was uses as an endpoint in this study. The
follow-up period for the study was 13 months. The results of the study
revealed that MTWA was present in 50 patients (49%), while LP was present in
21 patients (21%) and an ejection fraction of less than 40% in 28 patients
(27%). Using predictive values as well as a univariate Cox regression to
predict events, the following accuracy measures were obtained for the three
diagnostic measures:
|
Sensitivity |
Specificity |
PPV |
NPV |
RH |
p-value |
MTWA |
93% |
59% |
28% |
98% |
16.8 |
0.006 |
LP |
53% |
85% |
38% |
91% |
5.7 |
0.0008 |
EF |
60% |
78% |
32% |
92% |
4.7 |
0.004 |
The authors concluded that
because of the high values for sensitivity as well as negative predictive
value, MTWA could be used as a tool for screening patients for various serious
ventricular arrhythmias after a myocardial infarction. The author notes that
some limitations of the study include the fact that patients with a very low
EF (<20%) were excluded from the study. Also the results may not be
applicable to patients with significant accounts of ventricular ectopy or
abnormal heart rate variability.
In a second study, Ikeda and
associates again assessed T-wave alternans as a predictor for sudden cardiac
death after an MI (Ikeda, Saito, Tanno, Shimizu, Watanabi, Ohnishi, et al.
2002). This was a prospective study that recruited 850 consecutive MI patients.
Most of the participants (90%) underwent MTWA testing within 2 to 10 weeks of
the acute MI. In addition to MTWA, other prognostic indices used to predict
sudden death included ventricular late potentials (LP), and 40% left
ventricular ejection fraction (EF). Primary endpoints were prospectively
defined as sudden cardiac death (SCD), as well as VTE. Secondary endpoints
included sustained tachycardia. During the study a number of participants died
from non-arrhythmic causes. For the remaining 834 patients, the mean follow-up
period was 25 months. A total of 67 patients (8%) had arrhythmic events
(either primary or secondary endpoints). Of these patients, 3% reached 1 of
the primary endpoints, 12 died suddenly, and 13 had resuscitated VF while for
secondary endpoints, 5% had sustained VT. MTWA was positive in 36% of
participants, indeterminate in 12% and negative in 52% of participants. LP was
positive, and an abnormal EF was found in 18% of participants, and LP was
negative and the EF was normal in remaining 82% of participants. Of the 11
risk indices (e.g., gender, age, CABG, antiarrhythmic drug therapy, successful
percutaneous coronary intervention, LP, MTWA, EF), univariate analysis
revealed that MTWA predicted primary endpoints with a relative hazard ratio of
11.4, while the remainder risk indices had relative risk ratios varying
between 6.6 and 3.2. Using multivariate Cox regression, only MTWA and EF were
found to be significantly associated with primary endpoints. MTWA has the
highest sensitivity and NPV than either EF alone, or combined MTWA and EF.
|
Sensitivity |
Specificity |
PPV |
NPV |
RH |
p-value |
MTWA |
92% |
83% |
7% |
99% |
11.4 |
0.0001 |
EF |
56% |
83% |
9% |
98% |
6.6 |
0.0001 |
MTWA/EF |
52% |
92% |
18% |
98% |
11.9 |
0.0001 |
|
50% |
84% |
10% |
98% |
5.2 |
0.0002 |
The authors concluded that MTWA
and abnormal left ventricular ejection fraction were significant predictors of
sudden cardiac death or VF, where as LP by signal-averaged electrocardiography
and other prognostic indices failed to predict subsequent risk in this large
series of infarction survivors. One of the limitations of the study mentioned
by the authors is not including heart rate variability as a study variable. In
both studies, a spectral analysis algorithm was used as a protocol for MTWA
testing.
Because of the association
between VTEs and cardiac mortality, implanted cardiac defibrillators have been
used in patients at high risk of this condition. In 2003, CMS recommended
using QRS duration as a means to identify Multicenter Automatic Defibrillator
Implantation Trial II (MADIT II)-like patients suitable for implanted cardiac
defibrillators (ICD) therapy. Bloomfield and associates compared the ability
of MTWA (using a spectral analysis algorithm) and QRS duration to identify
groups at high risk and low risk of dying among heart failure patients who met
the MADIT II criteria for ICD prophylaxis (Bloomfield, Steinman, Namerow,
Parides, Davidenko, Kaufman, et al. 2004). The study enrolled 549 subjects, of
whom 177 had ischemic heart disease and an ejection fraction of < 30
percent, and also met other MADIT II criteria (> than 1 month after a
myocardial infarction, and > 3 months after coronary revascularization).
MTWA testing as well as QRS testing was performed on each participant, and
all-cause mortality was used as an endpoint. Based on the results of these
test, participants were placed in 1 of 4 groups: MTWA normal; MTWA abnormal;
QRS < 120 ms; QRS >120 ms. The results of the study revealed the
following: 32% of the MADIT II-like patients had a QRS duration of >120 ms,
and the MTWA test was abnormal in 68% of the patients. The 2-year actuarial
mortality rates for patients with positive and indeterminate MTWA test were
similar (14.5% and 20.1% respectively). For all 177 MADIT II-like patients,
the 2-year actuarial mortality rate was 13.2%. When analyzing the difference
in mortality between the 2 MTWA groups and the 2 QRS groups, the 2-year
actuarial mortality rate was substantially lower among patients with normal
MTWA test (3.8%), than among patients with a narrow QRS duration (12%),
corresponding to false negative rates of 3.5% and 10.2% respectively (see
below). A QRS duration >120 ms was weakly associated with MTWA status (OR
1.7, p=0.15). In a multivariate Cox model, MTWA remained a strong predictor of
mortality after adjusting for QRS duration (hazard ratio 4.7, p=0.012).
Measure |
MTWA |
QRS Duration |
Actuarial Mortality% |
||
Abnormal |
17.8 |
15.9 |
Normal |
3.8 |
12.0 |
Hazard Ratio |
4.8 |
1.5 |
Classified as low risk (%) |
32.2 |
68.2 |
False-negative rate (%) |
3.5 |
10.2 |
The data from this study
indicates that MTWA is a better than QRS duration in identifying high-risk
patients among those with ischemic heart disease and left ventricular ejection
fraction of < 30% who fit MADIT II criteria.
Cohen also investigated the usefulness
of MTWA in stratifying risk of the MADIT II population (Cohen, 2004). He
prospectively evaluated nine studies done previously which had evaluated
MTWA’s role in predicting occurrence of VTE. These studies included a variety
of patient populations (patients referred for electrophysiologic studies,
patients with CHF, patients with dilated cardiomyopathies, and patients with
myocardial infarctions), as well as a number of differing follow up periods
(ranged from 13 to 72 months). The results of the analysis revealed that
relative risk (RR) varied between 1.4 to 16.8 indicating that MTWA was an
effective non-invasive means of assessing which patients were at high risk and
low risk of VTE and sudden cardiac death. Cohen also noted a study performed
by Hohnloser and associates that reported on 129 MADIT II type patients drawn
from two previously published prospective studies which evaluated the use of
MTWA as a predictor of VTEs (Hohnloser, Ikeda, Bloomfield, Dabbous, Cohen,
2003). These patient had previously had myocardial infarctions as well as
ejection fractions < than 30%. This evaluation consisted of 87 patients
that were taken from the Ikeda and colleagues study (Ikeda, Saito, Tanno, et
al. 2002); while 42 participants were taken from the Klingenhaben and
colleagues study (Klingenheben, Zabel, D’Agostino, Cohen, Hohnloser 2000). The
primary endpoint of the study was sudden cardiac death. Sub-group analysis
revealed that in this population at 24 months of follow up, there was a 15.6%
rate of cardiac arrest and sudden cardiac death among participants that tested
positive or indeterminate for MTWA, compared with no events among patients
that tested negative for MTWA.
Grimm and colleagues evaluated a
number of variables which were felt important in determining arrhythmia risk
stratification for patients with dilated cardiomyopathy (Grimm, Christ, Bach,
Müller, Maisch 2003). These factors included left ventricular ejection
fraction and size by echocardiography, heart rate variability, baroreflex
sensitivity, SAE, arrhythmias on Holter ECG, QTc, and MTWA using a spectral
analysis algorithm. Of the 463 screen patients with IDC, 343 were enrolled,
and of this number 263 patients with sinus rhythm. During the 52 month
follow-up period, major arrhythmias were observed in 46 patients (13%),
including sudden cardiac death in 23 patients. A total of 49 patients (14%)
died during follow-up, and 10 patients (3%), underwent heart transplantation.
Major arrhythmic events occurred
in 38 (14%) of the 263 patients with sinus rhythm at study entry. Univariate
analysis revealed that left ventricular ejection fraction and diameter,
non-sustained VT, and frequent ventricular premature beats on a 24-hour Holter
ECG, and indeterminate MTWA were statistically associated with arrhythmic
events during follow up. But multivariate analysis revealed only left
ventricular ejection fraction was a significant predictor of major events
during follow-up, with a relative risk of 2.28 per 10% reduction of ejection
fraction. Multivariate analysis also revealed that left ventricular ejection
fraction was a significant predictor of transplantation-free survival, with a
relative risk of 2.51 per 10% decrease in ejection fraction. And for the 10%
of patients with ICDs and atrial fibrillation at the entry to the study,
multivariate analysis again revealed that left ventricular ejection fraction
and the lack of beta-blockers were significant predictors of major arrhythmic
events. Based on the multivariate analysis, MTWA was not found to be
statistically associated with arrhythmic risk stratification.
Grimm does note discrepancies in
results when compared to other studies evaluating the usefulness of MTWA. He
attributes differing results due to a differences in methods and patient
populations. In contrast to this study, other studies have used smaller
patient populations as well as other studies allowing patients with sustained
VT or VF. Also, Grimm notes that other studies most of the arrhythmic events
during follow-up occurred in patients who had already received an ICD before
study entry because of a history of sustained VT or cardiac arrest. The author
did note some limitations of this study included fact that the use of
beta-blockers was non-uniform and that many patients did not receive
beta-blockers at the entry of the study. He also noted that even though this
was a large study that included patients with Idiopathic cardiomyopathy for
risk stratification, the number of events in the MACAS study may still be too
small to exclude moderate relations of some of the variables tested to outcome
with certainty.
Modified Moving Average (MMA)
technique for determining MTWA
A review of the literature
failed to reveal any large studies using this technique to detect MTWA. One
commenter provided us with two articles on the use of MMA for MTWA detection.
One of the articles submitted was by Nearing et al. (Nearing, Verrier, 2002),
which describes the use of MMA analysis of MTWA to predict ventricular
fibrillation in 12 mongrel dogs. Another study submitted by the commenter used
a methodological framework to study principles of MTWA analysis (Martinez,
Olmos, 2005). This article only presented a methodological overview of the
different approaches to MTWA analysis. No information about study design,
sample size, inclusion/exclusion criteria, or results was supplied.
Included in the bibliography of
the latter article were two others studies which used MMA as a means of
predicting MTWA. In the first article the authors evaluated the effects of
acute mental stress and exercises on MTWA in patients with implantable
cardioverter defibrillators (Kop et al. 2004). This study did not use MMA as a
determinant of MTWA which would predispose patients to ventricular
tachyarrhythmic events. The second study used the MMA analysis to assess risk
of cardiac arrest or arrhythmia in postmyocardial infarction patients
(Verrier, Nearing, La Rovere et al. 2003). The authors used the MMA analysis
to measure MTWA magnitude in 24-hour ambulatory electrocardiogram recordings
from the Autonomic Tone and Reflexes after Myocardial Infarction study
(ATRAMI), a prospective study of 1,284 post MI patients. Using a nested
case-control approach with 44 total subjects, cases were defined as patients
who experienced cardiac arrest due to documented ventricular fibrillation or
arrhythmic deaths during the follow up period. Researchers analyzed 15 cases
and 29 controls matched for sex, age, site of MI, left ventricular ejection
fraction, use of thrombolytics, and beta-blocker therapy. The study was able
to demonstrate that 4 to 7 fold higher odds of life-threatening arrhythmias
were predicted by MTWA using MMA. We were able to communicate with the primary
author, who supplied us with results using measures of accuracy (sensitivity,
specificity, positive and negative predictive values) commonly used by those
authors who had reported results on the use of spectral analysis to assess
MTWA.
The author of the latter article
also submitted other studies using MMA to assess MTWA. One study evaluated
psychological effects on repolarization, and its impact on hemodynamic factors
(Lampert, Shusterman, Burg et. al. 2005). The study consisted of 33 subjects
with ICDs and a history of ventricular arrhythmia who underwent ambulatory ECG
monitoring during a laboratory mental stress protocol. The study revealed that
MTWA increased from 22 at baseline to 29 during mental stress. But limitations
of this study include the lack of a control group, as well as small sample
size. Another study submitted by the author assessed the degree of association
between MMA and spectral analysis in assessing MTWA (Hosteler, Xue, Young et
al. 2004). The study revealed a high degree of correlation between the two
technologies (between .92 and .99), but 22 data sets from ECG stress test, and
17 data sets from European Society of Cardiology (ESC) ST-T database were
used. No head-to-head comparisons in the clinical setting were performed. A
final study submitted by the author attempted to improve MTWA measurement
quality by reducing noise and artifact (Kaiser, Findeis, Young 2004).
Simulated ECGs with differing MTWA values, Holter ECGs from the ESC ST-T
database, and exercise ECGs were used as data sources. The study did reveal a
high sensitivity and specificity when compared to exercise ECGs and Holter ECGs,
but did note that despite the improved acceptance and rejection capability for
noise and artifact, noise related false positive MTWA values could not be
completely eliminated.
Another commenter mentioned the
use of the MMA as a means to measure MTWA, and supplied us with a list of
citations which included published articles and abstracts. Most of the
citations listed were addressed above (Nearing, Verrier, 2002; Martinez,
Olmos, 2005; Kop et al. 2004; Verrier, Nearing, La Rovere et 2003), though an
additional study was submitted using 16 adult mongrel dogs to measure MTWA and
vulnerability to ventricular fibrillation (Nearing, Huang, Verrier, 1991). As
noted above, results of animal studies are not generalizable to the Medicare
population. Another citation mentioned by the commenter pertains to the
pathophysiological and clinical applications of MTWA (Armoundas, Tomaselli,
Esperer, 2002). Though spectral analysis was discussed in this article, there
was no specific mention of the MMA technique for MTWA detection (the article
mentions several other computerized methods have been applied for detection
and quantification of MTWA such as autocorrelation techniques, complex
demodulation and autoregression techniques). Also the article fails to mention
any specific studies which used the MMA method, the study design, sample size,
inclusion/exclusion criteria, or study results. One additional citation
mentioned by the commenter compares spectral and time-domain techniques for
tracking temporal repolarization instabilities, using simulated signals with
changing heart rates, variable levels of MTWA, phase shifts, spurious
artifacts, and period-four oscillations, all based on real-life Holter data.
(Shusterman, Goldberg 2004). But as noted previously, no information on
measures of accuracy (sensitivity, specificity, positive and negative
predictors) were provided. No information was provided on study subjects,
research design, or pertinent information about clinical comparability, which
could help in determining which modality is more useful.
4. MCAC
A Medicare Coverage Advisory
Committee (MCAC) meeting was not convened on this issue.
5. Evidence-based guidelines
We did not find published
evidence-based guidelines for MTWA.
6. Professional Society Position Statements
There were no published position
statements on the use of MTWA as a diagnostic test from the American Heart
Association, the American College of Cardiologist, the Heart Rhythm Society,
or the American College of Chest Physicians. We did receive comments from
several professional societies during the public comment periods, as noted
below.
7. Expert Opinion
We have not currently received
any expert opinions on the use of MTWA testing for evaluating candidates for
ICD placement.
8. Public Comments
During the initial public
comment period, CMS received written statements from 28 sources including
practicing cardiologists, professors of medicine at various university
hospitals, cardiac devices manufacturers, and a summary comment from the
requestor. The initial public comments are available for review at: http://www.cms.hhs.gov/mcd/viewpubliccomments.asp?nca_id=165#0707200508072005
During the second public comment
period, CMS received written statements from 80 sources, representing a
similar cross-section of stakeholders as seen during the first comment period.
Comments from the second public comment period are available for review at: http://www.cms.hhs.gov/mcd/viewpubliccomments.asp?nca_id=165#1221200501212006
Comments about the evidence:
Comment:
Four
commenters stated that CMS should include the Modified Moving Average (MMA)
method of determining MTWA and included references to support their
recommendation. An additional four commenters believed CMS should include MMA,
but with evidentiary support. Four commenters stated that MMA should not be
covered nationally due to a lack of large scale studies.
Response:
A
review of the literature failed to reveal any large studies using the MMA
technique to detect MTWA. See sections entitled Modified Moving Average
(MMA) technique for determining MTWA in the Evidence section above and the
Analysis section below for a review of the evidence.
Comments about other aspects
of the decision memorandum:
Comment:
Among
the commenters, 54 stated that MTWA is effective for risk stratification prior
to ICD therapy and that the technology should be nationally covered. Of these
five stated that MTWA testing should be required prior to ICD implantation. An
additional 11 provided general support for the memorandum’s determination.
Response:
CMS
has determined that there is sufficient evidence to conclude that MTWA
diagnostic testing is covered for the evaluation of patients at risk of sudden
cardiac death. The test is not required prior to ICD implantation.
Comment:
CMS
received a combined comment from the Heart Rhythm Society and the American College
of Cardiology. In it, they stated that MTWA may become an important part of
patient management, but that the test should not be a prerequisite for
determining the appropriateness of ICD therapy. They went on to state that
additional prospective studies are needed to identify appropriate uses of MTWA
in various populations. CMS received comments from three device manufacturers.
One stated that although MTWA appears as a promising technology, the NCD
should be delayed until the results of an industry-sponsored clinical study
are released in late 2006. Since data are lacking on patients that are greater
than 20 months post-test, two device manufacturers believe that additional
time is needed to determine the long-term impact of a single negative MTWA test.
One party also believes the results of an on-going, industry-sponsored,
prospective clinical trial will assist physicians on the use and
interpretation of MTWA testing. A third device manufacturer agreed that MTWA
testing should not be required prior to ICD therapy, but that CMS should
delineate in its decision which patients may or may not be appropriate for
MTWA testing.
Response:
We
agree that there is not sufficient current evidence to require MTWA testing as
a prerequisite for ICD therapy. CMS encourages on-going study of MTWA to
further refine this technology and to inform physicians and patients on the
best use of MTWA diagnostic testing.
VIII. CMS Analysis
National coverage determinations
(NCDs) are determinations by the Secretary with respect to whether or not a
particular item or service is covered nationally under title XVIII of the
Social Security Act § 1869(f)(1)(B). In order to be covered by Medicare, an
item or service must fall within one or more benefit categories contained
within Part A or Part B, and must not be otherwise excluded from coverage.
Moreover, with limited exceptions, the expenses incurred for items or services
must be “reasonable and necessary for the diagnosis or treatment of illness or
injury or to improve the functioning of a malformed body member,” according to
§1862(a)(1)(A) of the Social Security Act. This section presents the agency’s
evaluation of the evidence considered and the conclusions reached for the
assessment questions.
1. Is the quality of evidence
adequate to conclude that MTWA testing can improve net health outcomes and is
reasonable and necessary for Medicare patients who are candidates for ICD
placement?
From the studies used to
evaluate this technology, it does appear that the quality of evidence is
adequate to conclude that MTWA testing using a spectral analysis algorithm can
improve net health outcomes, and is reasonable and necessary for Medicare
patients who are candidates for ICD placement. The reviewed literature
contains a number of studies evaluating the use of MTWA in a variety of
population settings, including subjects with congestive heart failure (CHF),
ischemic CHF, non-ischemic CHF, dilated cardiomyopathy, hypertrophic
cardiomyopathy, post MI, and in healthy subjects. The material reviewed included
not only small prospective studies with a homogenous patient population, but
also large systematic reviews with heterogeneous patient populations. Also
included in this analysis were studies that looked specifically at MTWA’s role
as a risk stratification tool in patient populations similar to those in both
MADIT II and SCD-HeFT.
A number of diagnostic tools are
available for risk assessment. Unfortunately, some of these tools have low
diagnostic usefulness. In order for a diagnostic test to be useful, it must be
able to demonstrate accuracy and reliability. Commonly used measures of
diagnostic accuracy include sensitivity, specificity, positive predictive
value (PPV), and negative predictive value (NPV). Though some of the studies
used in this assessment did not include these measures of accuracy, most did.
When reviewing these measures of accuracy, MTWA demonstrated superior findings
related to sensitivity and NPV when compared to other diagnostic tests used to
assess risk of VTEs.
Across a number of population
settings, MTWA consistently demonstrates superiority when compared to other
diagnostic measures that assess risk of VTEs. Though some of the studies noted
some limitations related to methodology as well as research design, these
limitations were not enough to invalidate their findings.
We reviewed the BCBSA technology
assessment. Both CMS and BCBSA use an evidenced-based medicine approach, based
on specific criteria, when assessing the effectiveness of technology. Though
both CMS and BCBSA have similar criteria for assessing technology, CMS must
also assure that the technology has demonstrated improved net outcomes within
the Medicare-eligible population.
Due to the unique
characteristics of the Medicare-eligible population (i.e. elderly, and more
likely to have multiple co-morbidities), sudden cardiac death has a higher
potential to occur as a result of VTE in this population. The potential harms
from adverse events are also more likely to occur within this population.
Because of these features of the Medicare population, the potential for
benefit or harm from ICD placement varies from that of the BCBSA population at
large, and plays a prominent role in our decision-making. Indications for ICD
placement also differ between the two organizations. Because of the higher
potential for VTE occurrence in the Medicare population, and because CMS
recognizes VTEs as an indication for ICD placement, CMS feels that the use of
MTWA is reasonable and necessary to address problems related to VTE and its
adverse consequences.
Based on this analysis, CMS has
determined that MTWA is a useful risk stratification tool and can identify
which heart patients are at negligible risk of sudden death, and who may
therefore be able to avoid ICD implantation and its attendant risks. Studies
have demonstrated that ICD implantation does improve survival in patients
prone to VTEs. Based on accuracy measures such as sensitivity and NPV, studies
have demonstrated that, when it is applied to appropriate target populations,
MTWA can identify those patients in which prophylactic ICD implantation is of
little benefit, as well as the patient populations in which ICD implantation
is beneficial.
However, CMS does not believe
that the evidence is sufficient to show that MTWA should be the only
diagnostic test for the purpose of stratifying high risk patients of VTE.
Physicians may choose to use a variety of other diagnostic testing to
elucidate the need for an ICD (e.g., left ventricular ejection fraction,
signal-averaged ECG, etc.). Also, we do not believe that the current evidence
is sufficient to require that physicians use the results of MTWA testing to
select appropriate patients for ICD implantation.
2. If the evidence is
adequate to conclude that MTWA testing can improve net health outcomes, what
characteristics of the test method, the pathologic condition, or the patient
can satisfactorily predict an improved health outcome?
Extensive clinical research has
revealed that patients with symptoms of or at risk of life threatening
arrhythmias who test positive for T-wave alternans are at a significant risk
for subsequent development of sudden cardiac events, including sudden death,
while those who test negative are a minimal risk. The use of MTWA using a
spectral analysis algorithm as a stratification tool can help to identify
patients in high risk population (e.g., those with ischemic and non-ischemic
cardiomyopathy, dilated cardiomyopathy, post myocardial infarction, MADIT
II-type, or SDC-HeFT-type) who are actually at low-risk for SCD. By applying
this diagnostic tool, it is possible to classify those who test positive or
indeterminate for MTWA (e.g., those more likely to benefit from ICD
implantation), and those who test negative for MTWA (e.g., those less likely
to benefit from ICD implantation).
The relevant evidence base for
the modified moving average (MMA) algorithm is comparatively small. Animal
studies (Kop et al. 2004; Nearing, Huang, Verrier, 1991) do not provide an
adequate surrogate for Medicare beneficiaries. Limitations of various
published reports on MMA include small sample sizes (Lampert, Shusterman, Burg
et. al. 2005; Verrier, Nearing, La Rovere et al. 2003), use of theoretical
models, simulations or non-clinical outcome measures (Martinez, Olmos, 2005;
Kaiser, Findeis, Young 2004; Shusterman, Goldberg 2004; Armoundas, Tomaselli,
Esperer, 2002), and the lack of control groups (Lampert, Shusterman, Burg et
al. 2005)
Results of the 2003 study by
Verrier, Nearing, La Rovere et al. suggest that the clinical information
provided by MMA is comparable in some respects to spectral analysis. Though
the sensitivity was moderate, the negative predictive value was equivalent to
findings using spectral analysis. Problems associated with this study include
small sample size (n =44), limitations of study design (e.g., potential for
survivor bias, the possibility that the observed associations are due to the
effects of confounding, and baseline measurements may be affected by silent
pre-clinical diseases.). In addition, the results also had large confidence
intervals, which might indicate imprecision and high variability. The author
informed us of an ongoing study employing the use of MMA for MTWA analysis.
That study has a much larger sample size, but the study has not been completed
yet. We look forward to reviewing it when it has been published in the
peer-reviewed medical literature.
In summary, the evidence base
supporting the spectral analysis method includes numerous trials that enrolled
adequate numbers of human subjects and used patient-relevant clinical outcome
endpoints. The evidence base for the MMA method is smaller, and though
suggestive of benefit, is not yet convincing. We believe that currently
available evidence only supports the use of spectral analysis algorithm for
the detection of MTWA.
IX. Conclusion
CMS has determined that there is
sufficient evidence to conclude that Microvolt T-wave Alternans (MTWA)
diagnostic testing is reasonable and necessary for the evaluation of patients
at risk of sudden cardiac death, only when the spectral analytic method is
used, and CMS is issuing the following national coverage determination (NCD)
for this indication.
Microvolt
T-wave Alternans (MTWA) diagnostic testing is covered for the evaluation of
patients at risk of sudden cardiac death, only when the spectral analytic
method is used.
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