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Why Microvolt T-Wave Alternans?

~10 million patients at elevated risk of SCD

450,000 sudden deaths per year1

~ONLY 100,000 patients receive life saving ICD therapy per year2

A need for a cost effective, efficient, tool for assessing risk of SCD.
1AHA
2003 Statistics
2IIndustry
Sources
Sudden Cardiac Death
A Major Public Health Problem

10 million
patients at
elevated risk for
SCD

400,000 deaths

1/7 of all deaths
FDA Cleared Indications
“FDA cleared indications support testing a wide spectrum
of patients the physician suspects are at risk of ventricular
tachyarrhythmias. “The presence of Microvolt T-Wave
Alternans as measured by the Analytic Spectral Method of
the [Heartwave System] in patients with known, suspected
or at risk of ventricular tachyarrhythmia predicts increased
risk of a cardiac event (ventricular tachyarrhythmia or
sudden death).”1
1
FDA 510(k) K013564, November 21, 2001
Clinical Applications

History indicating increased risk of sustained ventricular
arrhythmias
– Syncope, Pre-syncope, Palpitations
– Non-sustained VT
– Family History
– VT or VF associated with transient or reversible cause

Left Ventricular Dysfunction
– Heart failure
– Cardiomyopathy (Ischemic or Non-Ischemic)
– Ejection Fraction  0.40

Prior Myocardial Infarction
High Risk Groups for SCD
Population Size
SCD Percent / Year
Total SCD / Year
High Coronary
Risk
Post M I
Heart Failure/
E F < 35%)
Syncope /
Heart Disease
Previous
VF / VT
0
1
2
5
(millions)
10
20
0
1
2
5 10 20 50
(percent)
0
50
100
200
300
(thousands)
Adapted from Myerburg
Clinical Evidence
MGH/MIT Clinical Study
Design
83 consecutive patients referred for EP study
Alternans compared to EP as a predictor of
arrhythmia- free survival
Atrial pacing @ 100 BPM
Follow -up 20 months
Results
Patient Characteristics
Value
Prediction of
EPS
Events
Male / Female
59 / 24
Sensitivity
81%
89%
Age (±SD)
57±16
Specificity
84%
89%
PPV
NPV
Relative Risk
76%
88%
5.2
80%
94%
13.3
Indication for study
Sustained VT
Syncope
Cardiac arrest
Supraventricular arrhythmias
Symptomatic ventricular ectopy
Palpitations
Type of heart disease
Coronary artery disease
Dilated cardiomyopathy
31%
22%
20%
18%
7%
1%
64%
8%
Mitral-valve prolapse
4%
No organic heart disease
24%
Rosenbaum, Jackson, Smith, Garan, Ruskin, Cohen. NEJM 1994;330:235-41
MGH / MIT Study
EP Study
Negative
100
Arrhythmia-free Survival (%)
Arrhythmia-free Survival (%)
Alternans Test
80
60
Positive
40
RR =13.3
P<0.001
20
0
0
4
8
12
Months
16
20
Negative
100
80
60
Positive
40
RR =5.2
P<0.001
20
0
0
4
8
12
16
Months
Rosenbaum, Jackson, Smith, Garan, Ruskin and
Cohen N Engl J Med 1994;330:235-241
20
Frankfurt ICD Study
Design
95 consecutive patients receiving ICD’s
Risk stratification prior to implant:
TWA, EPS, LVEF, BRS, SAECG, HRV,
QT Dispersion, QTVI, Mean RR, NSVT
Endpoint: First appropriate ICD firing
Follow -up 18 months
Patient Characteristics
% Male
Age (±SD)
EF (±SD)
Value
81%
60±10
36 ±14
Index Arrhythmia
Ventricular fibrillation (VF)
VF/VT
Ventricular tachycardia (VT)
Nonsustained VT w/ syncope
38 (40%)
4 (4%)
45 (48%)
8 (8%)
Type of Heart Disease
Coronary artery disease
Dilated cardiomyopathy
Hypertrophic cardiomyopathy
Other
None
71 (75%)
16 (17%)
2 (2%)
1 ( 1%)
5 (5%)
Results
Follow-up 442±210 days
41 first appropriate ICD firings (34 for VT, 7 for
VF)
TWA (relative risk 2.5, p < 0.006) and LVEF
(relative risk 1.4, p < 0.04) were the only
statistically significant univariate predictors of
appropriate ICD firing during follow-up.
Cox regression analysis revealed that TWA
was the only statistically significant
independent predictor of appropriate ICD
firing.
TWA was highly predictive in the CAD
subgroup as well.
Hohnloser, Klingenheben, Li, Zabel, Peetermans, and Cohen.
J Cardiovasc Electrophysiol 1998; 9:1258-1268
Frankfurt ICD Study Results
EP Study
100
90
80
70
60
50
40
30
20
10
0
Event Free Survival
Event Free Survival
Alternans Test
TWA -
TWA +
P<0.006
Relative Risk 2.5
0
2
4
6
8
10
Months
12
14
16
18
100
90
80
70
60
50
40
30
20
10
0
EP -
EP +
P<0.23
Relative Risk 1.0
0
2
4
6
8
10
12
14
16
18
Months
Hohnloser, Klingenheben, Li, Zabel, Peetermans, and
Cohen. J Cardiovasc Electrophysiol 1998; 9:1258-1268
Multi-Center Regulatory Study
Design
337 patients referred for EP study
9 US Centers
Objective: Compare TWA predictive accuracy to EPS
Follow- up on 290 patients for 297 + 103 days
Endpoints: Ventricular tachyarrhythmic events(VTE),
VTE plus Total Mortality
Patient Characteristics
% Male
Age (±SD)
EF (±SD)
Value
64%
56±16
44 ±18%
Results
Probability of Probability of
Event
Event
(Positive)
(Negative)
Num ber
of Events
Relative
Risk
TWA
12
10.92
18.9%
1.7%
EPS
16
7.07
23.6%
3.3%
VT Events
Indication for EP
Syncope or Presyncope
Cardiac Arrest
Sustained VT
Non-Sustained VT
SVT
Other
41%
5%
14%
4%
31%
5%
Type of Heart Disease
Coronary artery disease
Dilated cardiomyopathy
Valvular heart disease
Other structural abnormality
No structural heart disease
46%
10%
11%
4%
30%
VT Events or Death
TWA
15
13.93
23.2%
1.7%
EPS
20
4.69
24.9%
5.3%
Gold MR, et al. JACC 2000: 36, 2247-53.
Multi-Center Regulatory Study
Alternans Test
EP Study
100
Event Free Survival
Event Free Survival
100
TWA -
90
80
70
TWA +
RR =13.9
P<0.001
60
50
90
EP -
80
RR=4.7
P=0.001
70
EP +
60
50
0
2
4
6
8
Months
10
12
14
0
2
4
6
8
10
12
14
Months
Gold MR, et al. JACC 2000: 36, 2247-53.
Syncope Study
Design
Multicenter study of patients undergoing EPS using standard protocols
Substudy of 121 pts referred for evaluation of unexplained syncope
Follow-up 12 months
Patient Characteristics
Age
Gender
EF  0.40
CAD
All
N=313
56 ± 15 years
64% male
45%
46%
Syncope
N=121
61± 15 years*
74% male*
49%
56%
Results
In patients with unexplained
syncope undergoing
electrophysiology testing, 11% will
have an arrhythmic event or death
in 12 months
TWA was a better predictor of
arrhythmic events and death than
inducible VT during EPS
Bloomfield DM, Gold MR, Anderson KP, Wilber DJ, El-Sherif N, Estes NAM, Groh WJ, Kaufman ES,
Greenberg ML, Rosenbaum DS, Dabbous O, Cohen RJ. AHA, 1999.
Syncope Substudy
100
TWA -
100
EP -
90
90
EP +
80
TWA +
80
70
70
60
60
RR = 4.4; P< 0.05
50
50
0
1
2
3
4
5
6
Months
7
8
9 10 11 12
0
1
2
3
4
5
6
7
8
9 10 11 12
Months
Bloomfield DM, Gold MR, Anderson KP, Wilber DJ, El-Sherif N, Estes
NAM, Groh WJ, Kaufman ES, Greenberg ML, Rosenbaum DS, Dabbous
O, Cohen RJ. AHA, 1999.
Frankfurt CHF Study
Design
107 consecutive CHF patients
Excluded recent MI and VT/VF patients
Tested for TWA, EF, SAECG, Mean RR, HRV, NSVT, BRS test performed
Endpoint: VT/VF, SCD
Patient Characteristics
Value
Results
% Male
80%
Sensitivity 100%
Age (±SD)
56±10
PPV 21%
EF (±SD)
28 ±7
TWA only significant predictor
TWA independent of EF
Heart Disease
Coronary artery disease
67%
Dilated cardiomyopathy
33%
Klingenheben T, Zabel M, D’Agostino RB, Cohen RJ,
Hohnloser SH. The Lancet 2000; 356: 651-652.
Frankfurt CHF Study
Alternans Test
100
Event Free Survival
TWA -
90
80
TWA +
70
60
P<0.001
50
0
4
8
12
16
20
24
Months
Klingenheben T, Zabel M, D’Agostino RB, Cohen RJ,
Hohnloser SH. The Lancet 2000; 356: 651-652.
Ikeda Post MI Study
Design
119 consecutive patients with acute MI
MTWA test at 20±6 (7 to 30 days) post-MI
Determinate results for TWA, SAECG and EF
in 102 patients
Endpoints: sustained VT, VF, sudden death
Follow-up: 13 ± 6 months
Patient Characteristics
Value
Male
83
Female
Age (±SD)
Ejection fraction (±SD)
19
60±9
49 ±9%
Primary PTCA
w/ Stent
98%
58%
Anterior wall MI
Inferior wall MI
Lateral wall MI
49%
34%
17%
Results
MTWA had the highest univariate relative risk (16.8)
compared to SAECG (5.7) and EF (4.7)
MTWA had the highest sensitivity (93%) compared to
SAECG (53%) and EF (60%).
MTWA negative patients had the lowest event rate
(2%) compared to SAECG (9%) and EF (8%).
MTWA alone had a PPV of 28%; combining TWA with
SAECG yielded the highest PPV (50%).
Patients receiving thrombolitic therapy
Ikeda T, Sakata T, Takami M et al. JACC 1999; 35:722-729.
Ikeda Post-MI Study
Event Free (%)
100
TWA -
80
TWA +
60
40
P = 0.0002
20
0
0
2
4
6
8
10
12
Months
Ikeda T, Sakata T, Takami M et al. JACC 1999; 35:722-729.
Non-Ischemic DCM Study
Design
126 non-ischemic DCM patients
Endpoints: VT, VF, SCD
Follow-up: 11.9 + 6.3 months
Risk Stratifiers: TWA, LVEF baroreceptor sensitivity, RR interval, HRV
Patient Characteristics Value
Results
% Male
77%
7.6% event rate in MTWA negative
Age (±SD)
55±11
30% event rate in MTWA positive
EF (±SD)
28.8 ± 11.5
ICD recipients
32
Conclusions: MTWA was the only statistically significant predictor of events.
Kllingenheben T, Bloomfield, D, Cohen, R, Hohnloser, S; Circ
Vol. 104 No. 17, abstract #3689, 2002
Klingenheben T, Cohen RJ, Peetermans JA, Hohnloser SH.
AHA, 1998.
Non-Ischemic DCM Study
Arrhythmia-Free Survival
Preliminary Results in 126 patients
100
90
TWA-
80
70
60
50
TWA+
P=0.05
31 30
24 19 17 15 12 TWA-
62 53
43 37 35 27 20 TWA+
0
6
3
9
12
15
18
Months
Kllingenheben T, Bloomfield, D, Cohen, R, Hohnloser, S;
Circ Vol. 104 No. 17, abstract #3689, 2002
Ikeda Post MI (Large Multicenter Prospective Study)
Design
Results
850 consecutive post MI patients
PPV: 18%
Endpoints: SCD & VT
NPV: 98%
Follow-up: 25 + 13 months
RR: 10
Risk Stratifiers: TWA, LP, EF, NSVT
Patient Characteristics
Value
# Male
711
Age
63 + 11
Conclusions:
MTWA measured in the late phase of MI is a strong risk stratifier for SCD
in infarct survivors.
Ikeda, T, Amer J Card, Vol. 89, 2002
Ikeda Post MI (Large Multicenter
Prospective Study)
Event Free Survival
1
.9
.8
TWA +
.7
TWA -
.6
0 4
8
12 16 20 24
Follow-Up in Months
Ikeda, T, Amer J Card, Vol. 89, 2002
MTWA in MADIT II Patients

MADIT II may radically change our approach to
identifying which patients need an ICD
– Patients with an ischemic cardiomyopathy and EF 
0.30
– There was a 31% reduction in mortality in patients
randomized to ICD

Many physicians want to further risk-stratify this
population to identify
– A high-risk group likely to benefit from ICD therapy
– A low risk group who may not benefit from ICD therapy
Bloomfield MADIT II substudy (Large Multicenter Prospective Study)
Design
Results
177 post MI patients with EF< 30%
Mortality Rate amongst
MTWA Negatives: 2.1%
Endpoints: All cause mortality
RR: 7.4
Follow-up: 16.2 + 7.0 months
Conclusions:
• MTWA positive patients had a substantially higher mortality (18.9%)compared to
MTWA negative group (7%)
• One-third of MADIT II patients had negative MTWA tests, had an excellent 2-year
survival, and therefore may not require ICD therapy.
Bloomfield, Circulation, 2004; 110: 1885-1889
Bloomfield MADIT II Patients
Bloomfield, Circulation, 2004; 110: 1885-1889
Hohnloser MADIT II Patients
Design
Results
129 post MI patients with EF< 30%
Event rate amongst MTWA
Negatives (primary endpoint): 0 %
Primary endpoints: Sudden cardiac Death
& resuscitated cardiac arrest
Secondary endpoint: Primary endpoint
plus sustained ventricular arrhythmia
Follow-up: 16.0 + 8.0 months
RR = 
Event rate amongst MTWA
Negatives (secondary endpoint):
5.7%
RR = 5.5
Conclusions:
In MADIT II population patients with negative MTWA had an extremely low 2-years
mortality rate
Hohnloser et al. Lancet, Vol. 362 July 2003
Hohnloser MADIT II Patients (primary end point)
QRS Width
100
TWA Neg
90
TWA Not Neg
80 P = 0.023
35
70 94
0
34
80
26
62
6
12
24
44
19 TWA Neg
34 TWA Not Neg
18 24
Months
Relative Risk = 
Event-Free Survival (%)
Event-Free Survival (%)
MTWA
100
90
QRS
120ms
ms
QRS <=
> 120
80 P = 0.78
80
70 37
0
73
32
59
24
45
19
35 QRS <= 120 ms
15 QRS > 120 ms
6
12
18 24
Months
Relative Risk at 24 months = 1.1
Hohnloser, Lancet, Vol. 362, July 2003
Hohnloser MADIT II Patients (secondary end point)
QRS Width
100
TWA Neg
90
80
70
TWA Not Neg
P = 0.01
60
35
50 94
0
32
73
24
53
6
12
22
37
19 TWA Neg
28 TWA Not Neg
18 24
Months
Relative Risk = 5.5
Event-Free Survival (%)
Event-Free Survival (%)
MTWA
100
90
QRS <= 120 ms
80
70
P = 0.023
60
80
50 37
0
QRS > 120 ms
34 QRS <= 120 ms
10 QRS > 120 ms
69
27
54
18
43
12
6
12
18 24
Months
Relative Risk = 2.0
Hohnloser, Lancet, Vol. 362, July 2003
Baravelli : Predictive Significance for SCD of Microvolt level T wave
Alternans in NYHA class II CHF patients: A Prospective study
Design
Results
73 patients in NYHA class II with LVEF of
<45%
MTWA was positive in 30 (41%)
patients, Negative in 26 (36%)
Ischemic and Non-ischemic
Cardiomyopathy
7 arrhythmic events in the MTWA
positive group
No events in the MTWA negative
group
Primary endpoint was SCD, documented
sustained VT/VF and appropriate ICD
shock
Follow-up 17.1±7.4 months
Sensitivity 100%
Specificity 53%
NPV 100%
PPV 24%
Conclusions:
Data suggests that MTWA is a promising predictor of arrhythmic events in NYHA class II
CHF patients.
Baravelli et al, International Journal of Cardiology, March
2005
Baravelli : Predictive Significance for SCD of Microvolt
level T wave Alternans in NYHA class II CHF patients: A
Prospective study
Baravelli et al, International Journal of Cardiology, March 2005
Baravelli : Predictive Significance for SCD of Microvolt
level T wave Alternans in NYHA class II CHF patients: A
Prospective study
Baravelli et al, International Journal of Cardiology, March 2005
Bloomfield Patients with Ischemic Heart Disease and Left Ventricular
Dysfunction
Design
Results
66% had abnormal MTWA test
Study conducted at 11 clinical centers in
U.S.
587 ischemic heart disease patients with
LVEF≤40
Primary endpoint all cause mortality or
non-fatal sustained ventricular
arrhythmias
20 ± 6 month follow-up
51 end points (40 deaths, and 11
non-fatal sustained ventricular
arrhythmias
HR was 6.5 at 2 years(95%
confidence interval, p<0.001)
Survival of -patients with normal
MTWA was 97.5% at 2 years
Conclusions:
Among patients with heart disease and LVEF ≤ 40, MTWA can identify not only a highrisk group, but also a low-risk group unlikely to benefit for ICD prophylaxis.
Bloomfield et al, Journal of the American College of
Cardiology, January 2006
Bloomfield Patients with Left
Ventricular Dysfunction
Bloomfield et al, Journal of the American College of
Cardiology, January 2006
Recent Clinical Review Papers

“T-Wave Alternans and the Susceptibility to Ventricular
Arrhythmias”, Sanjiv Narayan, MB. MD, Journal of the
American College of Cardiology, January 2006

“Can Microvolt T-wave Alternans Testing reduce
unnecessary defibrillator implantation?”, Antonis A.
Armoundas, Stefan H. Hohnloser, Takanori Ikeda, Richard
Cohen, Nature in Clinical Practice, October 2005
MTWA is a Powerful Arrhythmic Risk
Stratifier
Annual Spontaneous Ventricular Tachyarrhythmic Event Rates These rates were
observed in prospective natural history MTWA studies in patients similar to patients in
MADIT-II and SCD-HeFT.
Study
Population
N
Klingenheben,
2000
Hohnloser, 2003
Kitamura, 2002
Adachi, 2001
Grimm, 2003
CHF (Prior MI and
DCM)
DCM
DCM
DCM
DCM
LVEF  0.45
Prior MI
Prior MI
Prior MI
LVEF  0.30
Prior MI
LVEF  0.30
All
203
Ikeda, 2000
Ikeda, 2002
Hohnloser et al,
2003
Chow, 2003
All
MTWA+
MTWA-
HR
107
FollowUp
(months)
18
16%
0%

137
83
82
263
18
21
40
72
17%
16%
11%
3%
4%
2%
1%
2%
4
9
12
1.5
102
834
129
13
24
24
30%
4%
9%*
19%
2%
0.5%
0%*
3%
16
8
8%
1%
6
6
8.4%
1.2%
7
1,811
18

*SCD and Cardiac Arrest only
Antonis A. Armoundas, Stefan Hohnloser, Takanori Ikeda,
Richard J. Cohen, Nature Clinical Practice, October 2005
All Cause Mortality is Lower in MTWA Negative Patients Who Did Not
Receive ICDs than in Comparable Patients in the MADIT-II and SCDHeFT Trials who Did Receive ICDs
Annual All Cause Mortality Rates
Upper portion of table involves prospective ICD studies. Lower part of table
involves prospective MTWA studies in non-ICD patients with reported mortality
endpoint analyses.
Study
MADIT II2, 2002
SCDHeFT3, 2004
Population
Prior MI
LVEF  0.30
CHF
LVEF  0.35
All
N
1,232
Follow-Up
(months)
20
13.2%
9.2%
2,521
60
9.0%
6.5%
10.4%
7.4%
3,753
Study
Bloomfield9, 2003
Hohnloser et al17,
2003
Costantini et al,
2004
Grimm et al14,
2003
All
Population
Prior MI
LVEF  0.30
Prior MI
LVEF  0.30
DCM
LVEF  0.40
DCM
LVEF  0.45
N
Follow-Up
(months)
No ICD
Entire
Population
ICD
MTWA-
177
24
7%
2%
129
24
10%
7%
282
24
3%
0%
263
72
4%
2%
5.3%
2.0%
851
Antonis A. Armoundas, Stefan Hohnloser, Takanori Ikeda,
Richard J. Cohen, Nature Clinical Practice, October 2005