Why Microvolt T-Wave Why Microvolt T-Wave Alternans?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 DeathSudden Cardiac DeathA Major Public Health ProblemA Major Public Health Problem

10 million patients at elevated risk for SCD

400,000 deaths

1/7 of all deaths

FDA Cleared IndicationsFDA 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 ApplicationsClinical 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 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)

Adapted from Myerburg

Clinical EvidenceClinical Evidence

Rosenbaum, Jackson, Smith, Garan, Ruskin, Cohen. NEJM 1994;330:235-41

Design83 consecutive patients referred for EP studyAlternans compared to EP as a predictor of

arrhythmia- free survivalAtrial pacing @ 100 BPMFollow -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 76% 80%

Indication for study NPV 88% 94%

Sustained VT 31% Relative Risk 5.2 13.3

Syncope 22%

Cardiac arrest 20%

Supraventricular arrhythmias 18%

Symptomatic ventricular ectopy 7%

Palpitations 1%

Type of heart disease

Coronary artery disease 64%

Dilated cardiomyopathy 8%

Mitral-valve prolapse 4%

No organic heart disease 24%

MGH/MIT Clinical Study

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

RR =13.3P<0.001

RR =5.2P<0.001

Frankfurt ICD Study

Design95 consecutive patients receiving ICD’sRisk stratification prior to implant:

TWA, EPS, LVEF, BRS, SAECG, HRV, QT Dispersion, QTVI, Mean RR, NSVT

Endpoint: First appropriate ICD firingFollow -up 18 months

Patient Characteristics Value% Male 81%Age (±SD) 60±10EF (±SD) 36 ±14

Index ArrhythmiaVentricular fibrillation (VF) 38 (40%)VF/VT 4 (4%)Ventricular tachycardia (VT) 45 (48%)Nonsustained VT w/ syncope 8 (8%)

Type of Heart DiseaseCoronary artery disease 71 (75%)Dilated cardiomyopathy 16 (17%)Hypertrophic cardiomyopathy 2 (2%)Other 1 ( 1%)None 5 (5%)

Hohnloser, Klingenheben, Li, Zabel, Peetermans, and Cohen. J Cardiovasc Electrophysiol 1998; 9:1258-1268

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.

Frankfurt ICD Study ResultsFrankfurt ICD Study Results

EP Study

0102030405060708090

100

0 2 4 6 8 10 12 14 16 18

Months

Eve

nt

Fre

e S

urv

ival

TWA +

TWA -

Alternans Test

P<0.006Relative Risk 2.5

0102030405060708090

100

0 2 4 6 8 10 12 14 16 18

Months

Eve

nt

Fre

e S

urv

ival

EP +

EP -

P<0.23Relative Risk 1.0

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 Value Results% Male 64%Age (±SD) 56±16EF (±SD) 44 ±18%

Indication for EPSyncope or Presyncope 41%Cardiac Arrest 5%Sustained VT 14%Non-Sustained VT 4%SVT 31%Other 5%

Type of Heart DiseaseCoronary artery disease 46%Dilated cardiomyopathy 10%Valvular heart disease 11%Other structural abnormality 4%No structural heart disease 30%

Gold MR, et al. JACC 2000: 36, 2247-53.

Number of Events

Relative Risk

Probability of Event

(Positive)

Probability of Event

(Negative)VT Events

TWA 12 10.92 18.9% 1.7%

EPS 16 7.07 23.6% 3.3%

VT Events or Death

TWA 15 13.93 23.2% 1.7%

EPS 20 4.69 24.9% 5.3%

Multi-Center Regulatory Study Multi-Center Regulatory Study

Gold MR, et al. JACC 2000: 36, 2247-53.

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 Study

DesignMulticenter study of patients undergoing EPS using standard protocolsSubstudy of 121 pts referred for evaluation of unexplained syncopeFollow-up 12 months

Patient Characteristics

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

AllN=313

SyncopeN=121

Age 56 ± 15 years 61± 15 years*

Gender 64% male 74% male*

EF 0.40 45% 49%

CAD 46% 56%

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 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

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

Frankfurt CHF Study Frankfurt CHF Study

Klingenheben T, Zabel M, D’Agostino RB, Cohen RJ, Hohnloser SH. The Lancet 2000; 356: 651-652.

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

Ikeda Post MI Study

Design119 consecutive patients with acute MIMTWA test at 20±6 (7 to 30 days) post-MIDeterminate results for TWA, SAECG and EF in

102 patientsEndpoints: sustained VT, VF, sudden deathFollow-up: 13 ± 6 months

Patient Characteristics ValueMale

83Female 19Age (±SD) 60±9Ejection fraction (±SD) 49 ±9%

Primary PTCA 98%w/ Stent 58%

Anterior wall MI 49%Inferior wall MI 34%Lateral wall MI 17%

Patients receiving thrombolitic therapy

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%).

Ikeda T, Sakata T, Takami M et al. JACC 1999; 35:722-729.

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, Sakata T, Takami M et al. JACC 1999; 35:722-729.

Design126 non-ischemic DCM patients Endpoints: VT, VF, SCDFollow-up: 11.9 + 6.3 monthsRisk 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.

Klingenheben T, Cohen RJ, Peetermans JA, Hohnloser SH. AHA, 1998.

Non-Ischemic DCM Study

Kllingenheben T, Bloomfield, D, Cohen, R, Hohnloser, S; Circ Vol. 104 No. 17, abstract #3689, 2002

Non-Ischemic DCM StudyNon-Ischemic DCM StudyPreliminary Results in 126 patientsPreliminary Results in 126 patients

Kllingenheben T, Bloomfield, D, Cohen, R, Hohnloser, S; Circ Vol. 104 No. 17, abstract #3689, 2002

31 30 24 19 17 15 12 TWA-

62 53 43 37 35 27 20 TWA+

0 3 6 9 12 15 18

50

60

70

80

90

100

TWA-

TWA+P=0.05

Months

Arr

hyt

hm

ia-F

ree

Su

rviv

al

Ikeda Post MI (Large Multicenter Prospective Study)

Ikeda, T, Amer J Card, Vol. 89, 2002

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 Post MI (Large Ikeda Post MI (Large Multicenter Prospective Multicenter Prospective Study)Study)

1

.9

.8

.7

.6

0 4 8 12 16 20 24

Follow-Up in Months

Event F

ree Survival

TWA +

TWA -

Ikeda, T, Amer J Card, Vol. 89, 2002

MTWA in MADIT II PatientsMTWA 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)

Bloomfield, Circulation, 2004; 110: 1885-1889

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 MADIT II PatientsBloomfield MADIT II Patients

Bloomfield, Circulation, 2004; 110: 1885-1889

Hohnloser MADIT II Patients

Design

129 post MI patients with EF< 30%

Primary endpoints: Sudden cardiac Death & resuscitated cardiac arrest

Secondary endpoint: Primary endpoint plus sustained ventricular arrhythmia

Follow-up: 16.0 + 8.0 months

Hohnloser et al. Lancet, Vol. 362 July 2003

Results

Event rate amongst MTWA Negatives (primary endpoint): 0 %

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

MTWAMTWA

Relative Risk =

0 6 12 18 24

70

80

90

100

35 34 26 24 19 TWA Neg

TWA Neg

94 80 62 44 34 TWA Not Neg

TWA Not Neg

P = 0.023

Months

Eve

nt-

Fre

e S

urv

ival

(%

)

Relative Risk at 24 months = 1.1

QRS WidthQRS Width

0 6 12 18 24

70

80

90

100

80 73 59 45 35 QRS <= 120 ms

QRS <= 120 ms

37 32 24 19 15 QRS > 120 ms

QRS > 120 ms

P = 0.78

MonthsE

ven

t-F

ree

Su

rviv

al (

%)

Hohnloser, Lancet, Vol. 362, July 2003

Hohnloser MADIT II Patients Hohnloser MADIT II Patients (primary end point)(primary end point)

0 6 12 18 24

50

60

70

80

90

100

35 32 24 22 19 TWA Neg

TWA Neg

94 73 53 37 28 TWA Not Neg

TWA Not NegP = 0.01

Months

Eve

nt-

Fre

e S

urv

ival

(%

)

0 6 12 18 24

50

60

70

80

90

100

80 69 54 43 34 QRS <= 120 ms

QRS <= 120 ms

37 27 18 12 10 QRS > 120 ms

QRS > 120 ms P = 0.023

Months

Eve

nt-

Fre

e S

urv

ival

(%

)

MTWAMTWA QRS WidthQRS Width

Relative Risk = 5.5 Relative Risk = 2.0

Hohnloser MADIT II Patients Hohnloser MADIT II Patients (secondary end point)(secondary end point)

Hohnloser, Lancet, Vol. 362, July 2003

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

Design

73 patients in NYHA class II with LVEF of <45%

Ischemic and Non-ischemic Cardiomyopathy

Primary endpoint was SCD, documented sustained VT/VF and appropriate ICD shock

Follow-up 17.1±7.4 months

Baravelli et al, International Journal of Cardiology, March 2005

Results

MTWA was positive in 30 (41%) patients, Negative in 26 (36%)

7 arrhythmic events in the MTWA positive group

No events in the MTWA negative group

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

Baravelli et al, International Journal of Cardiology, March 2005

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

DesignStudy 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

Bloomfield et al, Journal of the American College of Cardiology, January 2006

Results

66% had abnormal MTWA test

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 high-risk group, but also a low-risk group unlikely to benefit for ICD prophylaxis.

Bloomfield Patients with Left Bloomfield Patients with Left Ventricular DysfunctionVentricular Dysfunction

Bloomfield et al, Journal of the American College of Cardiology, January 2006

Recent Clinical Review PapersRecent 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 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 ICDsICDs

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 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