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Why Microvolt T-Wave Alternans?

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

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Why Microvolt T-Wave Alternans?

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  1. 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

  2. Sudden Cardiac DeathA Major Public Health Problem • 10 million patients at elevated risk for SCD • 400,000 deaths • 1/7 of all deaths

  3. 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

  4. 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

  5. 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 50 100 200 300 20 0 1 2 5 10 0 1 2 5 10 20 50 (thousands) (percent) (millions) High Risk Groups for SCD Adapted from Myerburg

  6. Clinical Evidence

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

  8. Alternans Test Negative Negative Positive Positive MGH / MIT Study EP Study RR =13.3 P<0.001 RR =5.2 P<0.001 Rosenbaum, Jackson, Smith, Garan, Ruskin and Cohen N Engl J Med 1994;330:235-241

  9. 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 Value % Male 81% Age (±SD) 60±10 EF (±SD) 36 ±14 Index Arrhythmia Ventricular fibrillation (VF) 38 (40%) VF/VT 4 (4%) Ventricular tachycardia (VT) 45 (48%) Nonsustained VT w/ syncope 8 (8%) Type of Heart Disease Coronary artery disease 71 (75%) Dilated cardiomyopathy 16 (17%) Hypertrophic cardiomyopathy 2 (2%) Other 1 ( 1%) None 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

  10. Alternans Test 100 100 90 90 TWA - 80 EP - 80 70 70 60 60 Event Free Survival 50 Event Free Survival 50 40 EP + TWA + 40 30 P<0.006 Relative Risk 2.5 P<0.23 Relative Risk 1.0 30 20 20 10 10 0 0 0 2 4 6 8 10 12 14 16 18 0 2 4 6 8 10 12 14 16 18 Months Months Frankfurt ICD Study Results EP Study Hohnloser, Klingenheben, Li, Zabel, Peetermans, and Cohen. J Cardiovasc Electrophysiol 1998; 9:1258-1268

  11. 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±16 EF (±SD) 44 ±18% Indication for EP Syncope or Presyncope 41% Cardiac Arrest 5% Sustained VT 14% Non-Sustained VT 4% SVT 31% Other 5% Type of Heart Disease Coronary 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.

  12. Alternans Test EP Study TWA - EP - Event Free Survival Event Free Survival TWA + RR=4.7 P=0.001 RR =13.9 P<0.001 EP + Months Months Multi-Center Regulatory Study Gold MR, et al. JACC 2000: 36, 2247-53.

  13. Syncope Study • 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 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 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.

  14. TWA - EP - EP + Event Free Survival TWA + Event Free Survival RR = 4.4; P< 0.05 Months Months 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, 1999.

  15. 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.

  16. Alternans Test TWA - TWA + Event Free Survival Months Frankfurt CHF Study P<0.001 Klingenheben T, Zabel M, D’Agostino RB, Cohen RJ, Hohnloser SH. The Lancet 2000; 356: 651-652.

  17. 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 19 Age (±SD) 60±9 Ejection 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 Post MI Study Ikeda T, Sakata T, Takami M et al. JACC 1999; 35:722-729.

  18. TWA - TWA + Event Free (%) P = 0.0002 Months Ikeda Post-MI Study Ikeda T, Sakata T, Takami M et al. JACC 1999; 35:722-729.

  19. 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.

  20. Non-Ischemic DCM StudyPreliminary Results in 126 patients 100 90 TWA- Arrhythmia-Free Survival 80 70 TWA+ P=0.05 60 31 30 24 19 17 15 12 TWA- 50 62 53 43 37 35 27 20 TWA+ 0 3 6 9 12 15 18 Months Kllingenheben T, Bloomfield, D, Cohen, R, Hohnloser, S; Circ Vol. 104 No. 17, abstract #3689, 2002

  21. 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 CharacteristicsValue # 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

  22. Ikeda Post MI (Large Multicenter Prospective Study) 1 .9 .8 TWA + TWA - .7 Event Free Survival .6 0 4 8 12 16 20 24 Follow-Up in Months Ikeda, T, Amer J Card, Vol. 89, 2002

  23. 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

  24. 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

  25. Bloomfield MADIT II Patients Bloomfield, Circulation, 2004; 110: 1885-1889

  26. Hohnloser MADIT II Patients Results Event rate amongst MTWA Negatives (primary endpoint): 0 % RR =  Event rate amongst MTWA Negatives (secondary endpoint): 5.7% RR = 5.5 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 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

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

  28. Hohnloser MADIT II Patients (secondary end point) MTWA QRS Width Relative Risk = 5.5 Relative Risk = 2.0 Hohnloser, Lancet, Vol. 362, July 2003

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

  30. 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

  31. 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

  32. Bloomfield Patients with Ischemic Heart Disease and Left Ventricular Dysfunction 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 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 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 et al, Journal of the American College of Cardiology, January 2006

  33. Bloomfield Patients with Left Ventricular Dysfunction Bloomfield et al, Journal of the American College of Cardiology, January 2006

  34. 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

  35. MTWA is a Powerful Arrhythmic Risk Stratifier Antonis A. Armoundas, Stefan Hohnloser, Takanori Ikeda, Richard J. Cohen, Nature Clinical Practice, October 2005

  36. 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

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