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Micro Volt T Wave Alternans (MTWA)

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

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Micro Volt T Wave Alternans (MTWA)

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

  2. Microvolt 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?

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

  4. Even Beats Valt Mean Valt Odd Beats T-Wave Alternans

  5. 128 Beats Spectrum 50 Resp 40 30 Spectrum (V2) FFT Alternans 20 10 Noise 0 0.0 0.1 0.2 0.3 0.4 0.5 Frequency (Cycles/Beat) Spectral Method Detection of Microvolt TWA Beat Series Smith, Clancy, Valeri, Ruskin, and Cohen. Circulation 1988;77:110-121

  6. 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

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

  8. Do we need a better risk stratification method?

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

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

  11. 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 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.

  12. 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.

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

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

  15. 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

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

  17. Post MI & MTWA (Large Multicenter Study) Design • 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 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

  18. 850 pz. Post MI - 25 SCD & VF Events.( AJC Jan 2002)

  19. MTWA study in Athletes(F. Furlanello, G. Galanti,A. Michelucci, D. Marangoni, 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 EP 25 months follow up : no events in TWA- 1 ICD multiple discharges in TWA+ A.N.E. 2004 ;9(3):1-6

  20. MTWA with Exercise in Pediatrics and Congenital Heart Disease: Limitations and Predictive 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)

  21. Antiarrhythmic 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

  22. Beta 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.

  23. Event 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

  24. 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)

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

  26. 100 TWA - TWA Ind Arrhyth Survival 90 Pos vs. Neg: Hazard Ratio ~ , p < 0.05 TWA + 80 Total number of subjects at risk: 55 32 12 64 21 13 70 45 22 15 0 6 12 18 24 Months TWA in MADIT II Population: Multi-Center CHF Study2% death rate (twa-) comparared to 10% in ICD arm of Madit II Bloomfield, Daniel et alt Circulation 2004; 110:1885-1889

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

  28. 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

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

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

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

  32. 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

  33. 1 Year Total Mortality 20 TWA+ ICD- 14.7% ICD – 8.6% TWA- 7% TWA– 2.0% ICD+ 6.5% ICD– 12.4% TWA- 0% 15 ICD+ 7.3% 10 ICD+ 9.2% ICD- 5.6% 5 ICD+ 5.3% TWA- 0 Annualized mortality (%) TRIAL Chow6 - MADIT II1 SCD-Heft2 TWA-CHF3 TWA-CHF4 Hohnloser5 OHD NICM +EF < 0.40 ICM +EF < 0.30 ICM + EF < 0.35 ICM + NICM +EF < 0.35 ICM + EF < 0.30 ICM + EF < 0.40 FU(mo) 20 60 24 24 24 18 - 40 ANNUALIZED MORTALITY (%) • Costantini et al. Circulation 2004;110:667 (Supp) • Hohnloser et al Lancet 2003;362:125 • Chow et al. JACC 2006;47:1820 • Moss et al. NEJM 2002;346:877 • Bardy et al. NEJM 2005;352:225 • Bloomfield et al Circulation. 2004;110:1885

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

  35. 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)

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

  37. 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 .

  38. 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.”

  39. 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

  40. 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.

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

  42. ABCD TrialProtocolMUSTT population:400 patients, 42 Centers

  43. MASTER Trial on Madit II Patients • 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 study: • Post MI, EF <40%, Loop recorder implanted • 10 Centers, 400 Patients: end enrollement Dec. 2004

  44. Comparison to Other Risk MarkersPrediction of Arrhythmia-Free Survival

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

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

  47. Suggested protocols

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