Why Microvolt T-Wave Alternans? l ~10 million patients at elevated risk of SCD l 450,000 sudden deaths per year 1 l ~ONLY 100,000 patients receive life saving ICD therapy per year 2 l A need for a cost effective, efficient, tool for assessing risk of SCD. 1 AHA 2003 Statistics 2I Industry Sources

Sudden Cardiac Death A Major Public Health Problem l 10 million patients at elevated risk for SCD l 400,000 deaths l 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 l 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 l Left Ventricular Dysfunction –Heart failure –Cardiomyopathy (Ischemic or Non-Ischemic) –Ejection Fraction  0.40 l Prior Myocardial Infarction

High Risk Groups for SCD High Coronary Risk Post M I Heart Failure/ E F < 35%) Previous VF / VT Syncope / Heart Disease (thousands) (millions) Population Size SCD Percent / Year Total SCD / Year (percent) Adapted from Myerburg

Clinical Evidence

Rosenbaum, Jackson, Smith, Garan, Ruskin, Cohen. NEJM 1994;330: Design 83 consecutive patients referred for EP study Alternans compared to EP as a predictor of arrhythmia- free survival Atrial 100 BPM Follow -up 20 months Results Patient CharacteristicsValuePrediction ofEPSEvents Male / Female59 / 24Sensitivity81%89% Age (±SD)57±16Specificity84%89% PPV76%80% Indication for studyNPV88%94% Sustained VT31%Relative Risk Syncope22% Cardiac arrest20% Supraventricular arrhythmias 18% Symptomatic ventricular ectopy7% Palpitations1% Type of heart disease Coronary artery disease64% Dilated cardiomyopathy8% Mitral-valve prolapse4% No organic heart disease24% MGH/MIT Clinical Study

MGH / MIT Study EP StudyAlternans Test Negative Positive Negative Positive Rosenbaum, Jackson, Smith, Garan, Ruskin and Cohen N Engl J Med 1994;330: RR =13.3 P<0.001 RR =5.2 P<0.001

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 CharacteristicsValue % Male81% Age (±SD)60±10 EF (±SD)36 ±14 Index Arrhythmia Ventricular fibrillation (VF)38 (40%) VF/VT4 (4%) Ventricular tachycardia (VT)45 (48%) Nonsustained VT w/ syncope8 (8%) Type of Heart Disease Coronary artery disease71 (75%) Dilated cardiomyopathy16 (17%) Hypertrophic cardiomyopathy2 (2%) Other 1 ( 1%) None5 (5%) Hohnloser, Klingenheben, Li, Zabel, Peetermans, and Cohen. J Cardiovasc Electrophysiol 1998; 9: 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 Results EP Study Hohnloser, Klingenheben, Li, Zabel, Peetermans, and Cohen. J Cardiovasc Electrophysiol 1998; 9:

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 days Endpoints: Ventricular tachyarrhythmic events(VTE), VTE plus Total Mortality Patient CharacteristicsValueResults % Male64% Age (±SD)56±16 EF (±SD)44 ±18% Indication for EP Syncope or Presyncope41% Cardiac Arrest 5% Sustained VT14% Non-Sustained VT 4% SVT31% Other 5% Type of Heart Disease Coronary artery disease46% Dilated cardiomyopathy10% Valvular heart disease11% Other structural abnormality 4% No structural heart disease30% Gold MR, et al. JACC 2000: 36,

Multi-Center Regulatory Study Gold MR, et al. JACC 2000: 36, Alternans Test RR =13.9 P<0.001 Months Event Free Survival TWA + TWA - EP Study RR=4.7 P=0.001 Months Event Free Survival EP + EP -

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 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 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, TWA - TWA + RR = 4.4; P< 0.05 Event Free Survival Months EP - EP + Event Free Survival Months

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 CharacteristicsValueResults % Male80%Sensitivity 100% Age (±SD)56±10PPV 21% EF (±SD)28 ±7TWA only significant predictor TWA independent of EF Heart Disease Coronary artery disease67% Dilated cardiomyopathy33% Klingenheben T, Zabel M, D’Agostino RB, Cohen RJ, Hohnloser SH. The Lancet 2000; 356: Frankfurt CHF Study

Klingenheben T, Zabel M, D’Agostino RB, Cohen RJ, Hohnloser SH. The Lancet 2000; 356: Alternans Test TWA + TWA - Months Event Free Survival P<0.001

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 CharacteristicsValue Male83 Female19 Age (±SD)60±9 Ejection fraction (±SD) 49 ±9% Primary PTCA98% w/ Stent58% Anterior wall MI49% Inferior wall MI34% Lateral wall MI17% 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:

Ikeda Post-MI Study P = TWA - TWA + Event Free (%) Months Ikeda T, Sakata T, Takami M et al. JACC 1999; 35:

Design 126 non-ischemic DCM patients Endpoints: VT, VF, SCD Follow-up: months Risk Stratifiers: TWA, LVEF baroreceptor sensitivity, RR interval, HRV Patient CharacteristicsValueResults % Male77%7.6% event rate in MTWA negative Age (±SD)55±1130% event rate in MTWA positive EF (±SD)28.8 ± 11.5 ICD recipients32 Conclusions: MTWA was the only statistically significant predictor of events. Klingenheben T, Cohen RJ, Peetermans JA, Hohnloser SH. AHA, Non-Ischemic DCM Study Kllingenheben T, Bloomfield, D, Cohen, R, Hohnloser, S; Circ Vol. 104 No. 17, abstract #3689, 2002

Non-Ischemic DCM Study Preliminary Results in 126 patients Kllingenheben T, Bloomfield, D, Cohen, R, Hohnloser, S; Circ Vol. 104 No. 17, abstract #3689, TWA TWA TWA- TWA+ P=0.05 Months Arrhythmia-Free Survival

Ikeda Post MI (Large Multicenter Prospective Study) Ikeda, T, Amer J Card, Vol. 89, 2002 DesignResults 850 consecutive post MI patientsPPV: 18% Endpoints: SCD & VTNPV: 98% Follow-up: monthsRR: 10 Risk Stratifiers: TWA, LP, EF, NSVT Patient CharacteristicsValue # Male711 Age Conclusions: MTWA measured in the late phase of MI is a strong risk stratifier for SCD in infarct survivors.

Ikeda Post MI (Large Multicenter Prospective Study) Follow-Up in Months Event Free Survival TWA + TWA - Ikeda, T, Amer J Card, Vol. 89, 2002

MTWA in MADIT II Patients l 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 l 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: DesignResults 177 post MI patients with EF< 30%Mortality Rate amongst MTWA Negatives: 2.1% Endpoints: All cause mortality RR: 7.4 Follow-up: 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 Patients Bloomfield, Circulation, 2004; 110:

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: 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

MTWA Relative Risk =  Relative Risk at 24 months = 1.1 QRS Width Hohnloser, Lancet, Vol. 362, July 2003 Hohnloser MADIT II Patients (primary end point)

MTWA QRS Width Relative Risk = 5.5 Relative Risk = 2.0 Hohnloser MADIT II Patients (secondary end point) 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 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 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 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 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 Ventricular Dysfunction Bloomfield et al, Journal of the American College of Cardiology, January 2006

Recent Clinical Review Papers l “T-Wave Alternans and the Susceptibility to Ventricular Arrhythmias”, Sanjiv Narayan, MB. MD, Journal of the American College of Cardiology, January 2006 l “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 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 SCD- HeFT Trials who Did Receive ICDs Antonis A. Armoundas, Stefan Hohnloser, Takanori Ikeda, Richard J. Cohen, Nature Clinical Practice, October 2005