Transcript No Slide Title

Micro Volt T Wave Alternans
(MTWA)
( Analytic Spectral Method)
Microvolt T-Wave Alternans

What is TWA?

Published Clinical Data and ongoing trials

Suggested Clinical use protocols

How is an alternans test performed?

How is the test interpreted?
T-Wave Alternans
Visible
Predicts immediate
(VT/VF).
Microvolt Level
Measured with
proprietary spectral
method at heart rates.
Predicts ~2 year VT/VF.
T-Wave Alternans
Even Beats
Valt
Mean
Valt
Odd Beats
Spectral Method
Detection of Microvolt TWA
128 Beats
Beat Series
Spectrum
180
160
FFT
140
120
Spectrum ( V2)
T Wave Amplitude
200
50
Resp
40
30
20
Alternans
10
Noise
0
100
0
20
40
60
80
Beat Number
100
120
0.0
0.1
0.2
0.3
0.4
0.5
Frequency (Cycles/Beat)
Smith, Clancy, Valeri, Ruskin, and Cohen. Circulation 1988;77:110-121
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
(thousands)
300
Sudden Death Risk Factors
Trigger
LVEF/ MI
MTWA / Electr.
Instability
Do we need a better risk stratification method?
Microvolt T-Wave Alternans

What’s TWA

Published Clinical Data (all clinical data published
are based on Analytic Spectral Method)

Ongoing trials

Suggested Clinical Use Protocols

How is an alternans test performed?

How is the test interpreted?
MGH / MIT Study
EP Study
Negative
100
Arrhythmia-free Survival (%)
Arrhythmia-free Survival (%)
Alternans Test
80
60
Positive
40
20
0
0
4
8
12
Months
16
20
Negative
100
80
60
Positive
40
20
0
0
4
8
12
16
Months
Rosenbaum, Jackson, Smith, Garan, Ruskin and
Cohen N Engl J Med 1994;330:235-241
20
Multi-Center Regulatory Study
Prediction of VT/VF, ICD Firing and Total Mortality
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
Months
Gold MR, et al. A Comparison of TWA, SAECG, EP for
Arrhythmia Risk Stratif. JACC Vol 36,7,2000.
14
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
Preliminary Results in 81 patients
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 , Hohnloser SH. The Lancet Dec.
2000.
Non-Ischemic DCM Study
JACC 2003 Results in 137 patients
Kllingenheben T, Bloomfield, D, Cohen, R, Hohnloser, S;
JACC Vol 41 N.12 2003
Preditive value of MTWA Onset Heart Rate
Kitamura JACC Jan 2002: 104 DCM patients pts
Tanno, Circulation, 2004; 109: 1854-1858 on 248 ischemic and
non ischemic patients has found similar results
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,The American J. Cardiol Vol 89, Jan 1,2002
Post MI & MTWA (Large Multicenter Study)
Design

Prospective study, 834 consecutive patients, infarct
survivors, 7 Japanese centers.

Prognostic Indices: TWA, LP, EF, NSVT

Endpoint: SCD or resuscitated VF

Follow-up: 25 + 13 months
Conclusions: These findings from a large prospective study
demonstrate that TWA is a strong risk stratifier for sudden
cardiac death after myocardial infarction.
Ikeda, T,The American J. Cardiol Vol 89,
Jan 1,2002
850 pz. Post MI - 25 SCD & VF Events.
( AJC Jan 2002)
Sens.
NPV
RH
MTWA
22/24 (92%)
435/437(99%)
11
LVEF
14/25 (56%)
672/683(98%)
6
NSVT
12/25 (48%)
611/624(98%)
4
LP
11/22 (50%)
544/555(98%)
5
MTWA study in Athletes
(F. Furlanello, G. Galanti, A. Michelucci, D. Marangoni,
R. Cappato)

100 athletes ( no Organic Heart Disease)

48 healthy : 45 MTWA- 3 indeterm.

52 arrhythmic athletes
–
42 MTWA- (1 amiodaron) 3 indeterm.: 41 EP- (1 + amio)
–
7 MTWA+ :
• 5 EP+: 2 ICD 1Myocarditis 1 Amio 1 RFCA
• 1 EP- (but with NSVT)
• 1 no EP
25 months follow up : no events in TWA- 1 ICD multiple
discharges in TWA+
A.N.E. 2004 ;9(3):1-6
MTWA with Exercise in Pediatrics
and Congenital Heart Disease:
Limitations and Predictive Value

TWA is associated with pediatric and CHD
diagnoses at high risk of serious events
and may contribute, with other diagnostic
tools, to management choices.(Pacing
Clin Electrophysiol. 2006;29(7):733-741)
Antiarrhythmic Drug Study

49 patients w/ Cardiomiopathy and VT/VF

Class I and III antiarrhythmic drug (Amiodarone
57%)

Study endpoint: Recurrence of VT/VF in 13
months

Result: PPV 67% NPV 71%

Conclusion: TWA significantly predicts
reoccurrence of VT even on antiarrhythmic drug.
TWA may be also a useful marker for evaluating
the efficacy of antiarrhythmic drug
Koiki Sakabe A.N.E. 2001 6(3): 203-208
Beta Blocker Study

65 patients with prior VT

T-wave alternans measured atrial pacing at baseline
and during beta blockade with metoprolol and d,Isotalol

Both SOT and MET resulted in a reduced TWA
Amplitude but not in a change of TWA Onset HR.

Conclusion: There are comparable effects of SOT
and MET. TWA can be assessed during ongoing
therapy if target Heart Rate of 110bpm can be
reached.
Klikenhaben J Am Coll Card 2001;38:2013-9.
Event Rates of EPS and TWA
Singly
In Combination
EPS+
25%
EPS+, TWA+
39%
TWA+
25%
EPS-, TWA+
15%
EPS-
5%
EPS+, TWA-
12%
TWA- 1.5%
EPS-, TWA-
0%
Rashba, Gold MR, et al. . Enhanced vulnerability using TWA and EP
PACE 2002; 25(4,Part Ii): 523-750
MADIT II
(HF post MI with EF < 30%)

This study will increase the number
of ICD implanted from its current level of
60.000 by two fold to 120,000 (USA)- and
4 times in Europe.
SCD-Heft (EF <35%) will multiply again
the number of implants ( Class II on
Guidelines)
Ikeda AHA 2002 prospective study on MADIT II patients

VT and SD primary end points ;

1/25 negative TWA patient had Sustained VT but
no SD or VF
Data published on 129 pts with Hohnloser on The Lancet 2003; 362:125-26
TWA in MADIT II Population: Multi-Center CHF Study
2% death rate (twa-) comparared to 10% in ICD arm of Madit II
100
TWA TWA Ind
90
Pos vs. Neg:
Hazard Ratio ~ , p < 0.05
80
TWA +
Total number of subjects at risk:
55
32
64
21
70 45
22
0
6
12
Months
12
13
15
18
24
Bloomfield, Daniel et alt Circulation
2004; 110:1885-1889
Bloomfield MADIT II Patients
Bloomfield, Circulation, 2004; 110: 1885-1889
Baravelli and Salerno : 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
ICD placed / life saved

MADIT II

18 (11 at 3 yrs )

MTWA negative

-30%

MTWA positive

5

MUSTT

4
Data extracted from D. Bloomfield Circulation 2004
… Jacc 2006, Vol 47 N. 2 Daniel Bloomfield…

549 patients LVEF <40% (MADIT II and SCD-Heft
included)

2 years follow up

End points: death and Sustained VT/VF than
LVEF

“TWA was significantly better univariate and
multivariate predictor of death and Sustained
VT/VF”
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
1 Year
Total Mortality
Annualized
mortality
(%) II SCD-Heft TWA-CHF TWA-CHF
MADIT
TRIAL
OHD
ANNUALIZED MORTALITY (%)
FU(mo)
1.
2.
3.
1
ICM + EF < 0.30
20
2
ICM + NICM +
EF < 0.35
3
ICM + EF < 0.40
60
24
NICM +
EF < 0.40
24
4
Hohnloser5
ICM +
EF < 0.30
24
Chow6 ICM +
EF < 0.35
18 - 40
20
15
10
5
TWA+
ICD- 14.7%
ICD– 12.4%
ICD+ 9.2%
ICD – 8.6%
ICD+ 6.5%
TWA- 7%
ICD+ 7.3%
ICD- 5.6%
TWA– 2.0%
0
ICD+ 5.3%
TWA- 0%
TWAMoss et al. NEJM 2002;346:877
Bardy et al. NEJM 2005;352:225
Bloomfield et al Circulation. 2004;110:1885
4.
5.
6.
Costantini et al. Circulation 2004;110:667 (Supp)
Hohnloser et al Lancet 2003;362:125
Chow et al. JACC 2006;47:1820
Meta- Analysis on 2608 patients in
published trials.
( JACC 2005;46:75-82 )

Negative Predictive Value 97.2%

Positive Predictive Value 19.2%
ACC 2006 Investigator award
“Cost-effectiveness of ICD implantation
including the initial cost of ICD implant,
cost of MTWA testing, complications, ICD
replacements, death rates, etc.”

The results of the simulations revealed
an Incremental Cost Effectiveness Ratio
of $88,700 per Quality Adjusted Life Year
in the ICDs FOR ALL strategy as
compared to the use of MTWA risk
stratification. (JACC June 7 2006 ) and
confirmed by Dr MOSS study (JACC 2006;
47:2310-2318)
Costs of Healthcare will go outside national budgets so that
MEDICARE has DETERMINED that : “There is sufficient
evidence to conclude that microvolt TWA testing using only
the spectral analytic method can improve net health
outcomes and is reasonable and necessary for patients who
are candidates for ICD placement.“….
CMS proposes Medicare coverage for T-wave alternans ICD risk-stratification test
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“ MTWA 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 RISK”.
…..March 21, 2006
ICD risks :

“Prophylactic Defibrillator Therapy Is Associated
With Increased Mortality in Microvolt T-Wave
Alternans Negative Patients With Ischemic
Cardiomyopathy” (ACC 2005 abstract). Data
reported also in “Prognostic Utility of Microvolt TWave Alternans in Risk Stratification of Patients
With Ischemic Cardiomyopathy” JACC Vol 47, No
9 2006, May 2nd

”Frequency and causes of implantable
cardioverter-defibrillator therapies: is device
therapy proarrhythmic?”Am J Cardiol 2006 April
15 .
ACC/AHA/ESC 2006 NEW Guidelines for VA
& SCD patients (August 2006)
“ It is reasonable to use TWA for improving the
diagnosis and risk stratification of patients with
Ventricular Arrhythmias (VA) or who are at risk for
developing life threatening VA. Class IIa (Level of
Evidence A)”
“ICD trials especially MADIT II have highlighted the
need to develop novel tools in order to identify
patients at highest risk of VA and SCD.”
Mtwa icd strategy (1)
Clinical:

- class 2 applications (scd-heft)

- EF borderline

- help to increase the primary prevention
application penetration ( only 10% ) for
patients or doctors reluctant to ICD
implantation (for possible ICD / quality of life
complications)

- EP test cases of difficult interpretation
Mtwa icd strategy (2)
Economic Efficiency:

- not acceptable costs per quality
adjusted life year gain (50.000 $)

- budget limitation: not enough ICDs for
all primary (Class I) prevention
patients: A selection has to be made
also according to the new 2006
guidelines suggestions.
New trials with device implantation
to validate the positive predictive
value
ABCD Trial
Protocol
MUSTT population:400 patients, 42 Centers
CAD/NSVT
LVEF<40%
TWA/EP
TWA+/EP+
ICD
TWA+/EPSICD
TWA-/EP+
ICD
TWA-/EPNO ICD
MASTER Trial on Madit II Patients

Largest trial: 1800 patients

Post MI, EF<40% & Madit II & MTWA

ICD implanted in all MADIT II patients

60 Centers US: Start September 2003
CARISMA Northen Europe study:
• Post MI, EF <40%, Loop recorder implanted
•10 Centers, 400 Patients: end enrollement Dec. 2004
Comparison to Other Risk Markers
Prediction of Arrhythmia-Free Survival
Klingenheben et
al, 2000
*

Gold et al, 1999
Hohnloser et al,
1998
NSVT
HRV
SAECG
TWA
15
* p < 0.01
*
Armoundas et al,
1998
0
*
*
5
10
Relative Risk
Microvolt T-Wave Alternans

What’s TWA

Published Clinical Data and ongoing trials

Suggested Clinical Use Protocols

How is an alternans test performed?

How is the test interpreted?
Diagnosis and Treatment Model
High Risk Patients
Stress test with the CH 2000
Ischemia
T-wave Alternans
Coronary Angiography
Electrophysiology Study
CABG or Angioplasty
ICD, ablation, drugs
Suggested protocols
Patients with Known Heart Disease and
Unexplained Syncope
TWA
-
+
Look for other Causes
of Syncope
CAD
+
LVEF  0.40
EP
+
ICD
-
-
-
Loop Recorder
+
Consider ICD
Patients with Ischemic Heart Disease and LVEF  0.40
Stress Test with TWA
TWA+
Active Ischemia
TWA+
No Active Ischemia
TWANo Active Ischemia
Treat Ischemia
TWAActive Ischemia
Treat Ischemia
TWA +
Repeat TWA
EP
+
ICD
?
Microvolt T-Wave Alternans

What’s TWA

Published Clinical Data and ongoing trials

Suggested Clinical Use Protocols

How is an alternans test performed?

How is the test interpreted?
Heart Rate Dependence of TWA
ALTERNANS (mV)
40
J
VT PATIENT
CONTROL
30
J
20
J
H
10
J
0
80
JH
JH
H
H
100
120
140
HEART RATE (BPM)
Rosenbaum, et al
Measurement of TWA with CH-2000

Full featured stress
system

3 Pretest Lead checks

14 leads standard
stress test option

Proprietary Diagnostic
Screen Grid
New HearTwave II

Designed for best
MTWA testing.

Windows XP
operating system

Includes ECG
monitoring

Upgradeable to full
Stress test
Methods to increase Heart Rate

Treadmill or Ergometer

Pharmacologic (Dobutamine)

Pacing:
Atrial
AV Sequetial with AV delay of 180 msec
AV Simultaneous….
MTWA in Atrial Fibrillation patients

Microvolt T-wave alternans during exercise and pacing
in patients with acute myocardial infarction. PACE
2005;28:Suppl 1:S193-7.:
“Simultaneous V+A pacing can be used to assess TWA also
in patients with atrial fibrillation and impaired AV
nodal conduction. This approach also eliminates
retrograde atrial activation and/or random sinus
activity at descending portion of the T wave, which
may obscure the TWA analysis during ventricular
pacing. The data obtained with V+A pacing were
similar to those measured during the bicycle exercise
and A pacing “
High-Resolution Electrodes
Make noninvasive test feasible
ECG (Center)
Adaptive cancellation
reduces noise due to
patient movement
ECG (Segment)
Impedance
Respiration
Noise Reduction
Noise Reduced
Microvolt T-Wave Alternans

What’s new?

How are EPs using the test clinically?

How is an alternans test performed?

How is the test interpreted?
Positive TWA Test
(automatic interpretation)
Heart
Rate
T-Wave
Alternans
• Sustained Alternans
• Valt  1.9 µV
• Alternans ratio  3
• Positive HR threshold
• Onset HR < 110 bpm
Negative TWA Test
(automatic interpretation)
Heart
Rate
• No Sustained Alternans
• HR of > 105 achieved
T-Wave
Alternans
www.alternans.org
All updated information on T Wave
Alternans