1. Micro Volt T Wave Alternans (MTWA) ( Analytic Spectral Method)

2. Microvolt T-Wave Alternans l What is TWA? l Published Clinical Data and ongoing trials l Suggested Clinical use protocols l How is an alternans test performed? l How is the test interpreted?

3. T-Wave Alternans Visible Microvolt Level Predicts immediate (VT/VF). Measured with proprietary spectral method at heart rates. Predicts ~2 year VT/VF.

4. T-Wave Alternans Even Beats Odd Beats Mean V alt

6. Beat Series 128 Beats FFT Spectrum Alternans 0 10 20 30 40 50 0.00.10.20.30.40.5 Frequency (Cycles/Beat) Spectrum (  V 2 ) Resp Noise Spectral Method Detection of Microvolt TWA Smith, Clancy, Valeri, Ruskin, and Cohen. Circulation 1988;77:110-121

7. High Risk Groups for SCD High Coronary Risk Post M I Heart Failure/ E F < 35%) Previous VF / VT Syncope / Heart Disease 010020030050 (thousands) (millions) Population Size 0102050125 SCD Percent / Year Total SCD / Year 010125 20 (percent)

8. Sudden Death Risk Factors Sudden Death Risk Factors MTWA / Electr. Instability LVEF/ MI Trigger

9. Do we need a better risk stratification method?

10. Microvolt T-Wave Alternans l What’s TWA l Published Clinical Data (all clinical data published are based on Analytic Spectral Method) l Ongoing trials l Suggested Clinical Use Protocols l How is an alternans test performed? l How is the test interpreted?

11. MGH / MIT Study EP StudyAlternans Test Negative Positive Negative Positive Rosenbaum, Jackson, Smith, Garan, Ruskin and Cohen N Engl J Med 1994;330:235-241

12. Multi-Center Regulatory Study Prediction of VT/VF, ICD Firing and Total Mortality Gold MR, et al. A Comparison of TWA, SAECG, EP for Arrhythmia Risk Stratif. JACC Vol 36,7,2000. 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 -

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

14. Frankfurt CHF Study Preliminary Results in 81 patients Klingenheben, Hohnloser SH. The Lancet Dec. 2000. Alternans Test TWA + TWA - Months Event Free Survival P<0.001

15. Non-Ischemic DCM Study JACC 2003 Results in 137 patients Kllingenheben T, Bloomfield, D, Cohen, R, Hohnloser, S; JACC Vol 41 N.12 2003

16. 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

17. Ikeda Post-MI Study P = 0.0002 TWA - TWA + Event Free (%) Months Ikeda, T,The American J. Cardiol Vol 89, Jan 1,2002

18. Post MI & MTWA (Large Multicenter Study) l Prospective study, 834 consecutive patients, infarct survivors, 7 Japanese centers. l Prognostic Indices: TWA, LP, EF, NSVT l Endpoint: SCD or resuscitated VF l 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

19. 850 pz. Post MI - 25 SCD & VF Events. ( AJC Jan 2002) 850 pz. Post MI - 25 SCD & VF Events. ( AJC Jan 2002) Sens. NPV RH MTWA22/24 (92%) 435/437(99%) 11 LVEF14/25 (56%) 672/683(98%) 6 NSVT12/25 (48%) 611/624(98%) 4 LP11/22 (50%) 544/555(98%) 5

20. MTWA study in Athletes (F. Furlanello, G. Galanti, A. Michelucci, D. Marangoni, R. Cappato) l 100 athletes ( no Organic Heart Disease) l 48 healthy : 45 MTWA- 3 indeterm. l 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

21. MTWA with Exercise in Pediatrics and Congenital Heart Disease: Limitations and Predictive Value l 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)

22. Antiarrhythmic Drug Study l 49 patients w/ Cardiomiopathy and VT/VF l Class I and III antiarrhythmic drug (Amiodarone 57%) l Study endpoint: Recurrence of VT/VF in 13 months l Result: PPV 67% NPV 71% l 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

23. Beta Blocker Study l 65 patients with prior VT l T-wave alternans measured atrial pacing at baseline and during beta blockade with metoprolol and d,I-sotalol l Both SOT and MET resulted in a reduced TWA Amplitude but not in a change of TWA Onset HR. l 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.

24. Event Rates of EPS and TWA SinglyIn 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

25. 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)

26. Ikeda AHA 2002 prospective study on MADIT II patients Data published on 129 pts with Hohnloser on The Lancet 2003; 362:125-26 l VT and SD primary end points ; l 1/25 negative TWA patient had Sustained VT but no SD or VF

27. TWA in MADIT II Population: Multi-Center CHF Study 2% death rate (twa-) comparared to 10% in ICD arm of Madit II 06121824 Months 70 80 90 100 Arrhyth Survival 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

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

29. 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

30. ICD placed / life saved l MADIT II l MTWA negative l MTWA positive l MUSTT l 18 (11 at 3 yrs ) l -30% l 5 l 4 Data extracted from D. Bloomfield Circulation 2004

32. … Jacc 2006, Vol 47 N. 2 Daniel Bloomfield… l 549 patients LVEF <40% (MADIT II and SCD-Heft included) l 2 years follow up l End points: death and Sustained VT/VF than LVEF l “TWA was significantly better univariate and multivariate predictor of death and Sustained VT/VF”

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

34. 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

35. Annualized mortality (%) TRIAL OHD FU(mo) 0 5 10 15 20 MADIT II 1 ICM + EF < 0.30 20 SCD-Heft 2 ICM + NICM + EF < 0.35 60 TWA-CHF 3 ICM + EF < 0.40 24 TWA-CHF 4 NICM + EF < 0.40 24 Hohnloser 5 ICM + EF < 0.30 ICD– 12.4% ICD – 8.6% ICD+ 6.5% TWA– 2.0% TWA- 0% TWA- 7% ICD+ 9.2% 1. 1.Moss et al. NEJM 2002;346:877 2. 2.Bardy et al. NEJM 2005;352:225 3. 3.Bloomfield et al Circulation. 2004;110:1885 ANNUALIZED MORTALITY (%) 24 Chow 6 - ICM + EF < 0.35 18 - 40 ICD- 5.6% ICD+ 5.3% ICD- 14.7% ICD+ 7.3% TWA+ TWA- 4. 4.Costantini et al. Circulation 2004;110:667 (Supp) 5. 5.Hohnloser et al Lancet 2003;362:125 6. 6.Chow et al. JACC 2006;47:1820 1 Year Total Mortality

36. Meta- Analysis on 2608 patients in published trials. ( JACC 2005;46:75-82 ) l Negative Predictive Value 97.2% l Positive Predictive Value 19.2%

37. 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) (JACC June 7 2006 )(JACC 2006; 47:2310-2318)

38. CMS proposes Medicare coverage for T-wave alternans ICD risk-stratification test Dec 30, 2005Dec 30, 2005 Steve StilesSteve 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

39. ICD risks : l “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 l ”Frequency and causes of implantable cardioverter-defibrillator therapies: is device therapy proarrhythmic?”Am J Cardiol 2006 April 15.

40. 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.”

41. 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) l - EP test cases of difficult interpretation

42. 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.

43. New trials with device implantation to validate the positive predictive value

44. ABCD Trial Protocol MUSTT population:400 patients, 42 Centers

45. MASTER Trial on Madit II Patients MASTER Trial on Madit II Patients l Largest trial: 1800 patients l Post MI, EF<40% & Madit II & MTWA l ICD implanted in all MADIT II patients l 60 Centers US: Start September 2003 CARISMA Northen Europe study: Post MI, EF <40%, Loop recorder implanted Post MI, EF <40%, Loop recorder implanted 10 Centers, 400 Patients: end enrollement Dec. 200410 Centers, 400 Patients: end enrollement Dec. 2004

46. Comparison to Other Risk Markers Prediction of Arrhythmia-Free Survival

47. Microvolt T-Wave Alternans l What’s TWA l Published Clinical Data and ongoing trials l Suggested Clinical Use Protocols l How is an alternans test performed? l How is the test interpreted?

48. Diagnosis and Treatment Model High Risk Patients Stress test with the CH 2000 Electrophysiology Study Coronary Angiography ICD, ablation, drugs CABG or Angioplasty Ischemia T-wave Alternans

49. Suggested protocols

51. Microvolt T-Wave Alternans l What’s TWA l Published Clinical Data and ongoing trials l Suggested Clinical Use Protocols l How is an alternans test performed? l How is the test interpreted?

52. Heart Rate Dependence of TWA VT PATIENT H H HHH J J J J JJ 0 10 20 30 40 ALTERNANS (  V  HEART RATE (BPM) 80100120140 CONTROL Rosenbaum, et al

53. Measurement of TWA with CH-2000 l Full featured stress system l 3 Pretest Lead checks l 14 leads standard stress test option l Proprietary Diagnostic Screen Grid

54. New HearTwave II l Designed for best MTWA testing. l Windows XP operating system l Includes ECG monitoring l Upgradeable to full Stress test

55. Methods to increase Heart Rate l Treadmill or Ergometer l Pharmacologic (Dobutamine) l Pacing: Atrial AV Sequetial with AV delay of 180 msec AV Simultaneous….

56. 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 “

57. ECG (Segment) Impedance Respiration ECG (Center) Noise Reduced Adaptive cancellation reduces noise due to patient movement Noise Reduction High-Resolution Electrodes Make noninvasive test feasible

58. Microvolt T-Wave Alternans l What’s new? l How are EPs using the test clinically? l How is an alternans test performed? l How is the test interpreted?

59. Positive TWA Test (automatic interpretation) Heart Rate T-Wave Alternans Sustained Alternans V alt  1.9 µV Alternans ratio  3 Positive HR threshold Onset HR < 110 bpm

60. Negative TWA Test (automatic interpretation) Heart Rate T-Wave Alternans No Sustained Alternans HR of > 105 achieved

61. www.alternans.org All updated information on T Wave Alternans