micro volt t wave alternans (mtwa)

Micro Volt T Wave Micro Volt T Wave Alternans (MTWA)Alternans (MTWA)

( Analytic Spectral Method)

Microvolt T-Wave AlternansMicrovolt 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 AlternansT-Wave Alternans

VisibleVisible

Microvolt LevelMicrovolt Level

Predicts immediate Predicts immediate (VT/VF).(VT/VF).

Measured with Measured with proprietary spectral proprietary spectral method at heart rates. method at heart rates.

Predicts ~2 year VT/VF.Predicts ~2 year VT/VF.

T-Wave AlternansT-Wave Alternans

Even Beats

Odd Beats

MeanValt

Valt

100

120

140

160

180

200

0 20 40 60 80 100 120

Beat Number

T W

ave

Am

plit

ude

Beat Series

128 Beats

FFT

Spectrum

Alternans

0

10

20

30

40

50

0.0 0.1 0.2 0.3 0.4 0.5

Frequency (Cycles/Beat)Sp

ectr

um

(

V2 )

Resp

Noise

Spectral Method Spectral Method Detection of Microvolt TWADetection of Microvolt TWASpectral Method Spectral Method Detection of Microvolt TWADetection of Microvolt TWA

Smith, Clancy, Valeri, Ruskin, and Cohen. Circulation 1988;77:110-121

High Risk Groups for SCDHigh Risk Groups for SCD

High Coronary High Coronary RiskRisk

Post M IPost M I

Heart Failure/Heart Failure/E F < 35%)E F < 35%)

Previous Previous VF / VTVF / VT

Syncope /Syncope /Heart DiseaseHeart Disease

00 100100 200200 3003005050

(thousands)(thousands)(millions)(millions)

Population SizePopulation Size

00 1010 2020 505011 22 55

SCD Percent / YearSCD Percent / Year Total SCD / YearTotal SCD / Year

00 101011 22 55 2020

(percent)(percent)

Sudden Death Risk FactorsSudden Death Risk Factors

MTWA / Electr. Instability

LVEF/ MI Trigger

Do we need a better risk stratification Do we need a better risk stratification method?method?


What’s TWA

Published Clinical Data (all clinical data published are based on Analytic Spectral Method)

Ongoing trials

Suggested Clinical Use Protocols



MGH / MIT StudyMGH / MIT Study

EP StudyAlternans Test

0

20

40

60

80

100

0 4 8 12 16 20

Months

Arr

hyth

mia

-free

Sur

viva

l (%

)

Negative

Positive

0

20

40

60

80

100

0 4 8 12 16 20

Months

Arr

hyth

mia

-free

Sur

viva

l (%

)

Negative

Positive

Rosenbaum, Jackson, Smith, Garan, Ruskin and Rosenbaum, Jackson, Smith, Garan, Ruskin and Cohen Cohen N Engl J Med N Engl J Med 1994;330:235-2411994;330:235-241

Multi-Center Regulatory Study Multi-Center Regulatory Study Prediction of VT/VF, ICD Firing and Total Prediction of VT/VF, ICD Firing and Total MortalityMortality

Gold MR, et al. A Comparison of TWA, SAECG, EP for Arrhythmia Risk Stratif. JACC Vol 36,7,2000.

50

60

70

80

90

100

0 2 4 6 8 10 12 14

Alternans Test

RR =13.9P<0.001

Months

Eve

nt

Fre

e S

urv

ival

TWA +

TWA -

50

60

70

80

90

100

0 2 4 6 8 10 12 14

EP Study

RR=4.7P=0.001

MonthsE

ve

nt

Fre

e S

urv

iva

l

EP +

EP -

Syncope SubstudySyncope Substudy

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.

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12

TWA -

TWA +

RR = 4.4; P< 0.05

Eve

nt

Fre

e S

urv

i val

Months

EP -

EP +

Eve

nt

Fr e

e S

urv

i val

Months

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12

Frankfurt CHF Study Frankfurt CHF Study Preliminary Results in 81 patientsPreliminary Results in 81 patients

Klingenheben , Hohnloser SH. The Lancet Dec. 2000.

50

60

70

80

90

100

0 4 8 12 16 20 24

Alternans Test

TWA +

TWA -

Months

Eve

nt

Fre

e S

urv

ival

P<0.001

Non-Ischemic DCM StudyNon-Ischemic DCM StudyJACC 2003 JACC 2003 Results in 1 Results in 13737 patients patients

Kllingenheben T, Bloomfield, D, Cohen, R, Hohnloser, S;

JACC Vol 41 N.12 2003

Preditive value of MTWA Onset Heart Preditive value of MTWA Onset Heart

RateRate Kitamura JACC Jan 2002: 104 DCM patients pts

Tanno, Circulation, 2004; 109: 1854-1858 on 248 Tanno, Circulation, 2004; 109: 1854-1858 on 248 ischemic and non ischemic patients has found ischemic and non ischemic patients has found

similar resultssimilar results

Ikeda Post-MI StudyIkeda Post-MI Study

0

20

40

60

80

100

0 2 4 6 8 10 12

P = 0.0002

TWA -

TWA +

Eve

nt

Fre

e (%

)

Months

Ikeda, T,The American J. Cardiol Vol 89, Jan 1,2002

Post MI & MTWA (Large Multicenter Post MI & MTWA (Large Multicenter Study)Study)

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

Design

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 - 25 850 pz. Post MI - 25 SCD & VF SCD & VF EventEventss..( AJC Jan 2002)( 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 AthletesMTWA study in Athletes (F. Furlanello, G. Galanti,(F. Furlanello, G. Galanti, A. Michelucci, D. A. Michelucci, D.

Marangoni,Marangoni, R. Cappato) 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 EP25 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 MTWA with Exercise in Pediatrics and Congenital Pediatrics and Congenital Heart Disease: Limitations and Heart Disease: Limitations and Predictive ValuePredictive 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 StudyAntiarrhythmic 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 StudyBeta Blocker Study 65 patients with prior VT

T-wave alternans measured atrial pacing at baseline and during beta blockade with metoprolol and d,I-sotalol

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 TWAEvent 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 IIMADIT 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 Ikeda AHA 2002 prospective study on MADIT II patientsII patients

Data published on 129 pts with Hohnloser on The Lancet 2003; Data published on 129 pts with Hohnloser on The Lancet 2003; 362:125-26362:125-26

VT and SD primary end points ;

1/25 negative TWA patient had Sustained VT but no SD or VF

TWA in MADIT II Population: Multi-Center TWA in MADIT II Population: Multi-Center CHF CHF StudyStudy

2% death rate (twa-) comparared to 10% in ICD arm 2% death rate (twa-) comparared to 10% in ICD arm of Madit IIof Madit II

0 6 12 18 24Months

70

80

90

100A

rrh

yth

Su

rviv

al TWA -

TWA +

TWA Ind

55 32 12

Pos vs. Neg: Hazard Ratio ~ , p < 0.05

45 22 15

Total number of subjects at risk:

64 21 13

Bloomfield, Daniel et alt Circulation 2004; 110:1885-1889

Bloomfield MADIT II PatientsBloomfield MADIT II Patients

Bloomfield, Circulation, 2004; 110: 1885-1889

Baravelli and Salerno : Predictive Baravelli and Salerno : Predictive Significance for SCD of Microvolt level T Significance for SCD of Microvolt level T wave Alternans in NYHA class II CHF wave Alternans in NYHA class II CHF patients: A Prospective studypatients: A Prospective study

Baravelli et al, International Journal of Cardiology, March 2005

ICD placed / life savedICD placed / life saved

MADIT II

MTWA negative

MTWA positive

MUSTT

18 (11 at 3 yrs )

-30%

5

4

Data extracted from Data extracted from D. Bloomfield Circulation D. Bloomfield Circulation 20042004

… … Jacc 2006, Vol 47 N. 2 Daniel Jacc 2006, Vol 47 N. 2 Daniel

Bloomfield…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 MTWA is a Powerful Arrhythmic Risk StratifierRisk 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 Follow-

Up (months)

MTWA+ MTWA- HR

Klingenheben, 2000

CHF (Prior MI and DCM)

107 18 16% 0%

Hohnloser, 2003 DCM 137 18 17% 4% 4 Kitamura, 2002 DCM 83 21 16% 2% 9 Adachi, 2001 DCM 82 40 11% 1% 12 Grimm, 2003 DCM

LVEF 0.45 263 72 3% 2% 1.5

Ikeda, 2000 Prior MI 102 13 30% 2% 16 Ikeda, 2002 Prior MI 834 24 4% 0.5% 8 Hohnloser et al, 2003

Prior MI LVEF 0.30

129 24

9%* 19%

0%* 3%

6

Chow, 2003 Prior MI LVEF 0.30

203 18 8% 1% 6

All All 1,811 8.4% 1.2% 7

*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 All Cause Mortality is Lower in MTWA Negative Patients Who Did Not Receive ICDs than in Comparable Patients Who Did Not Receive ICDs than in Comparable Patients in the MADIT-II and SCD-HeFT Trials who Did Receive in the MADIT-II and SCD-HeFT Trials who Did Receive

ICDsICDsAnnual 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 Population N Follow-Up

(months) No ICD ICD

MADIT II2, 2002 Prior MI LVEF 0.30

1,232 20 13.2% 9.2%

SCDHeFT3, 2004 CHF LVEF 0.35

2,521 60 9.0% 6.5%

All 3,753 10.4% 7.4%

Study Population N Follow-Up (months)

Entire Population

MTWA-

Bloomfield9, 2003 Prior MI LVEF 0.30

177 24 7% 2%

Hohnloser et al17, 2003

Prior MI LVEF 0.30

129 24 10% 7%

Costantini et al, 2004

DCM LVEF 0.40

282 24 3% 0%

Grimm et al14, 2003

DCM LVEF 0.45

263 72 4% 2%

All 851 5.3% 2.0%

Antonis A. Armoundas, Stefan Hohnloser, Takanori Ikeda, Richard J. Cohen, Nature Clinical Practice, October 2005

Annualized Annualized mortality (%)mortality (%)TRIAL

OHD

FU(mo)

0

5

10

15

20

MADIT IIMADIT II11

ICM + EF < 0.30

20

SCD-HeftSCD-Heft22

ICM + NICM +EF < 0.35

60

TWA-CHFTWA-CHF33

ICM + EF < 0.40

24

TWA-CHFTWA-CHF44

NICM +EF < 0.40

24

HohnloserHohnloser55

ICM + EF < 0.30

ICD– 12.4%

ICD – 8.6% ICD+ 6.5%

TWA– 2.0% TWA- 0%

TWA- 7% ICD+ 9.2%

1. Moss et al. NEJM 2002;346:8772. Bardy et al. NEJM 2005;352:2253. Bloomfield et al Circulation. 2004;110:1885

AN

NU

AL

IZE

D M

OR

TA

LIT

Y (

%)

24

ChowChow66 - -

ICM + EF < 0.35

18 - 40

ICD- 5.6% ICD+ 5.3%

ICD- 14.7%

ICD+ 7.3%

TWA+TWA+

TWA-TWA-

4. Costantini et al. Circulation 2004;110:667 (Supp)5. Hohnloser et al Lancet 2003;362:1256. Chow et al. JACC 2006;47:1820

1 Year Total Mortality

Meta- Analysis on 2608 Meta- Analysis on 2608 patients in published trials.patients in published trials.

( JACC 2005;46:75-82 )( JACC 2005;46:75-82 )

Negative Predictive Value 97.2%

Positive Predictive Value 19.2%

ACC 2006 Investigator ACC 2006 Investigator awardaward

“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)

CMS proposes Medicare coverage for T-wave alternans ICD risk-stratification test

Dec 30, 2005

Steve Stiles

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.“….

“ 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 :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 T-Wave 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 ACC/AHA/ESC 2006 NEW Guidelines for VA & SCD patients Guidelines for VA & SCD patients

(August 2006)(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)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)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 New trials with device implantation to validate the implantation to validate the

positive predictive valuepositive predictive value

ABCD TrialABCD TrialProtocolProtocol

MUSTT population:400 patients, 42 MUSTT population:400 patients, 42 CentersCenters

C A D /N S V T

T W A + /E P +IC D

T W A + /E P S -IC D

T W A -/E P +IC D

T W A -/E P -N O IC D

L V E F< 4 0%T W A /E P

MASTER Trial on Madit II MASTER Trial on Madit II PatientsPatients

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 CARISMA Northen Europe study:study:• Post MI, EF <40%, Loop recorder Post MI, EF <40%, Loop recorder implantedimplanted

•10 Centers, 400 Patients: end enrollement 10 Centers, 400 Patients: end enrollement Dec. 200Dec. 20044

Comparison to Other Risk Comparison to Other Risk MarkersMarkersPrediction of Arrhythmia-Free SurvivalPrediction of Arrhythmia-Free Survival

Comparison to Other Risk Comparison to Other Risk MarkersMarkersPrediction of Arrhythmia-Free SurvivalPrediction of Arrhythmia-Free Survival

0 5 10 15

Relative Risk

Armoundas et al,

1998

Hohnloser et al,

1998

Gold et al, 1999

Klingenheben etal, 2000

NSVT

HRV

SAECG

TWA

*

*

*

*

* p < 0.01


What’s TWA





Diagnosis and Treatment Diagnosis and Treatment ModelModelDiagnosis and Treatment Diagnosis and Treatment ModelModel

High Risk PatientsHigh Risk PatientsHigh Risk PatientsHigh Risk Patients

Stress test with the CH 2000Stress test with the CH 2000Stress test with the CH 2000Stress test with the CH 2000

Electrophysiology StudyElectrophysiology StudyElectrophysiology StudyElectrophysiology StudyCoronary AngiographyCoronary AngiographyCoronary AngiographyCoronary Angiography

ICD, ablation, drugsICD, ablation, drugsICD, ablation, drugsICD, ablation, drugsCABG or AngioplastyCABG or AngioplastyCABG or AngioplastyCABG or Angioplasty

IschemiaIschemia T-wave AlternansT-wave Alternans

C A D L o o k fo r o th er C a u seso f S y n co p e

E P L V E F 0 .4 0

IC D L o o p R eco rd er C o n sid er IC D

+ -

+ -

+ - - +

T W A

P atien ts w ith K n ow n H eart D isease an dU n exp la in ed S yn cop e

Suggested Suggested protocolsprotocols

S tress T est w ith T W A

T W A +A ctiv e Isch em ia

T W A +N o A ctiv e Isch em ia

T W A -N o A ctiv e Isch em ia

T W A -A ctiv e Isch em ia

T rea t Isch em ia

R ep ea t T W A

E P

T rea t Isch em ia

T W A +

IC D ?

+ -

P a tien ts w ith Isch em ic H ea rt D isea se a n d L V E F 0 .4 0


What’s TWA





Heart Rate Dependence Heart Rate Dependence of TWAof TWAHeart Rate Dependence Heart Rate Dependence of TWAof TWA

VT PATIENTVT PATIENT

H

HHHH

J

J

J

J

JJ0

10

20

30

40

AL

TE

RN

AN

S (

V

HEART RATE (BPM)80 100 120 140

CONTROLCONTROL

Rosenbaum, et al

Measurement of TWA with Measurement of TWA with CH-2000 CH-2000

Full featured stress system

3 Pretest Lead checks

14 leads standard stress test option

Proprietary Diagnostic Screen Grid

New HearTwave IINew HearTwave II

Designed for best MTWA testing.

Windows XP operating system

Includes ECG monitoring

Upgradeable to full Stress test

Methods to increase Heart Methods to increase Heart RateRate

Treadmill or Ergometer

Pharmacologic (Dobutamine)

Pacing:

Atrial

AV Sequetial with AV delay of 180 msec

AV Simultaneous….

MTWA in Atrial Fibrillation MTWA in Atrial Fibrillation patientspatients

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 “

ECG (Segment)ECG (Segment)

ImpedanceImpedance

RespirationRespiration

ECG (Center)ECG (Center)

Noise ReducedNoise Reduced

Adaptive cancellation reduces noise due to patient movement

Adaptive cancellation reduces noise due to patient movement

Noise ReductionNoise Reduction

High-Resolution ElectrodesHigh-Resolution ElectrodesMake noninvasive test feasibleMake noninvasive test feasibleHigh-Resolution ElectrodesHigh-Resolution ElectrodesMake noninvasive test feasibleMake noninvasive test feasible


What’s new?

How are EPs using the test clinically?



Positive TWA TestPositive TWA Test (automatic interpretation)(automatic interpretation)

HeartRate

T-WaveAlternans

• Sustained Alternans• Valt 1.9 µV• Alternans ratio 3• Positive HR threshold

• Onset HR < 110 bpm

Negative TWA Test Negative TWA Test (automatic interpretation)(automatic interpretation)

HeartRate

T-WaveAlternans

• No Sustained Alternans

• HR of > 105 achieved

www.alternans.owww.alternans.orgrg

All updated information on T Wave Alternans

micro volt t wave alternans (mtwa)

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