1. APPROACHES TO THE PREVENTION OF SUDDEN DEATH How Well Do ICDs Work ? Gianluca Botto, MD, FESC Sant’ Anna Hospital, Como

2. 15 min

3. Treatment Group Mortality in the Placebo Arm of Val-HeFT 23-Month Mean Follow-up Treatment Group Mortality in the Placebo Arm of Val-HeFT 23-Month Mean Follow-up Courtesy Prof. JN Cohn

4. ICD Rx in Primary & Secondary Prevention Effect on Total Mortality Lee DS JACC 2003; 41: 1573 Relative Reduction = 25% Absolute Reduction = 7% Number Need to Treat = 15 Relative Reduction = 25 Absolute Reduction = 8% Number Need to Treat = 12 Nanthakumar K. JACC 2004; 44: 2166-72

5. MADIT II Long-Term 8-Year All-Cause Mortality Non-ICD 49% 62% FU 8 ys 0,52 LYS AR = 13% NNT = 8 Efficacy Analysis HR 0.66 (0.56-0.78) The long-term benefit was also evident in an ITT analysis. P= 0.017 FU 20 ms 0,17 LYS AR = 6% NNT = 17

6. Number Needed to Treat to Save One Life (5 Yr) (3 Yr) (3.8 Yr) (3 Yr) (3 Yr) (4 Yr) (1 Yr) (2 Yr) (1 Yr) (6 Yr) (5 Yr) (30 dy) NNT x years = 100 / (%Mortality in Control Group – %Mortality in Treatment Group) Botto GL It Heart J 2005; 6: 210-215 modif. ICD Therapy Drug Therapy

7. CABG (Chronic CAD, mild angina, 3 VD) Hypertension therapy (Diastolic 95-104 mmHg) Pre Prticipation Screening (Young Athlets) PTCA (Chronic CAD, mild angina, 1 VD) Primary coronary stenting (CAD, Angina, 1 VD, Male, age 55) Incremental Cost-Effectiveness of ICD Therapy and Other Cardiovascular Interventions Expensive Borderline Cost-effective Cost-Effective Highly Cost-Effective Incremental Cost per Life-Year Saved Economically Unattractive ICD AVID Lovastatin (chol. = 290 mg/dL, 50 yrs old, male, no risk factors) ICD- MADIT (Transvenous) ICD- MADIT II Various Articles 2010

8. ICD Drugs Giant stadium NY ICD In Severe LV Disfunction “…the game was stopped at the 5 th inning because of obvious superiority of the antagonist (i.e. ICD)

9. U.S. HF Device Market Adoption - 2008 IndicationsNet Prevalence ICD onlyCRT-P – CRT-D Estimated Adoption Secondary Prevention (SCA/VF/VT) 246.000230.00016.00082% Genetics (HCMP, LQTS, etc) 88.000 NA20% SCD-HeFT 534.000 NA22% High Risk Post MI (MADIT, MUSTT, MADIT II) 116.000 NA22% MIRACLE & COMPANION 396.000NA396.00031% Total Indicate Pts 1,380.000968.000412.000~35% Courtesy of E. Pristowsky

10. Real World Example of Inadequate Access to Rx for Patients Overall percent of eligible pts receiving an ICD was 35,4 % - white man 43,6% - black men 33,4% - white women 29,8% - black women 29,8 Eligible ICD candidate hospitalized for HF N=13.034 Hernandez JAMA 2007; 298: 1525-32 Less than 40% of potentially eligible pts hospitalized for HF received ICD Rx. Rate of use were lower among women and black patients

12. Source: EHRA Whitebook 2009 Median 99/ mio (Range 0,6- 470/ mio) na

13. Merkely B. EUROPACE 2010

14. Connolly SJ et al. Eur Heart J 2000;21:2071-2078 ICD: Cumulative Survival Regarding EF AMIO ICD

15. EF is NOT The Ideal Risk Stratification Test For Deciding Whether to Implant an ICD for Preventing SCD

16. Oregon Cardiac Arrest Registry 48% of Known EF ICD Indicated 30% N° of SCA Patients Daubert JP. HRS Late Breacking Trials 2008

17. Limitation of EF in Predicting SCD EF is a direct measure of contractile dysfunction EF only indirectly probes the underlying electrophysiological substrate of SCD EF is inherently NON-specific for predicting patients at risk for SCD EF should have a very high SS and SP and predictive accuracy that remains stable stable over time However …

18. Total Mortality, Arrhythmic Death / CA Relation with EF Buxton AE. Circulation 2002; 102: 2466-2472

19. Cost-Effectiveness of ICD Therapy Role of Mortality Rate and Mode of Death Cowie RM. Europace 2009; 11: 716-726

20. Patients (%) 15.9% 36.8% 11.5% Mortality 45.5 months (3.8 years) Poole JE. N Engl J Med 2008; 359: 1009

21. I’m sure you’ll hear all the virtues of methods to further risk stratify patients at risk for SCD N°Test (+)Test (-)RR (+/-)OR LVEF729420,04,74.35.1 SA-ECG988319,34,04.85.7 SVA956413,44,72.93.2 HRV571925,85,54.76.3 EPS402225,53,96.68,.5 Bailey JJ. J Am Coll Cardiol 2001; 38: 1902-11 modif. MTWA 17,8 3,8 Reduced EF is single most important RF for overall mortality and SD

22. Negative TWA Identifies a Low Risk Group Among Patients With Heart Failure of Nonischemic Aetiology Salerno-Uriarte JA. J Am Coll Cardiol 2007; 50: 1896 Total Mortality Arrhythmic Death or Life Threatening Arrhythmias

23. How Strong a RF is Necessary to Discriminate Pts @ Risk for SCD ? Probability Distibutions of a Marker Pepe MS. Am J Epidemiology 2004; 159: 882-890

24. Deliver ICD Therapy to Those Who Need It Costantini O. The ABCD Trial JACC 2009; 53: 471-9 (modif.) “Trade-off” B/ween Therapeutic Efficiency and Risk

25. VHR Group 60 of 1232 pts (4.8 %) BUN ≥ 50 mg/dl and/or Creat. ≥ 2.5 mg/dl Risk Stratification in MADIT-II Survival in Very High Risk Patients Goldenberg I. JACC 2008; 51: 288-96

26. Risk Stratification in MADIT-II Probability of Survival in Intermediate Risk Pts Goldenberg I. JACC 2008; 51: 288-96 EF ≤ 25% Age ≥ 72 ys Atrial fibrillation NYHA III-IV Creatinine ≥ 1.4 mg/dl QRS > 0.13 2 Risk Factors 1 Risk Factors

27. Risk Stratification in MADIT-II Probability of Survival in Very Low and High Risk Patients Goldenberg I. JACC 2008; 51: 288-96 EF ≤ 25% Age ≥ 72 ys Atrial fibrillation NYHA III-IV Creatinine ≥ 1.4 mg/dl QRS > 0.13 ≥ 3 Risk Factors ≥ 0 Risk Factors

28. U-Shaped Curve for ICD Efficacy Goldenberg I, et al. J Am Coll Cardiol 2008; 51: 288

29. Risk Stratification in MADIT-II Predictors of Long-Term Mortality (655 pts – 9-year follow-up) VariablesHR95% CIP value Diabetes1.361.07-1.740.012 AF (Non SR) 1.531.12-1.950.003 Age > 651.571.23-1.98<0.001 NHYA > II1.781.44-2.31<0.001 BUN > 28 mg/dl 2.201.69-2.79<0.001 Cygankiewicz I. Heart Rhythm 2009: 6: 468-473

30. ICER of ICD Tx by Age Subgroup Chan PS. Circ Cardiovasc Qual Outcomes 2009; 2: 16-24 965 Primary prevention pts With or w/out ICD (51/49%) Follow-up 34±16 mos ICD reduced death by 31% Comorbidity score - Symptomatic HF - Diabete - AF - PVD - COPD - Prior stroke - Renal Failure - Prior syncope

31. Atrial Fibrillation in ICDs Recipients Effects on Mortality Deneke T. Europace 2004; 6: 151-158

32. Frequency of Appropriate ICD Tx in Patients with or with/out Worsening of RF Takahashi A. Europace 2009; 1: 1476-1482

33. Cost-Effectiveness of ICD Rx by Age Chan PS. Circ Cardiovasc Qual Outcomes 2009; 2: 16-24

34. Mortality in Pts with CKD and ICD Tx Serum Creatinine / Estimated GFR Korantzopoulos P. Europace 2009; 11: 1469-1475

35. Bai R. – Natale A. J Cardiovasc Electrophysiol 2008; 19: 1259-1265 After CRT implant, chronic renal failure, diabetes mellitus, and history of AF are strong independent predictors of death Mortality in HF Pts After CRT Identification of Predictors Mortality in HF Pts After CRT Identification of Predictors

36. Acute Device Complications Among 17.804 Patients Swindle JP. Arch Intern Med 2010: 170: 631-637

37. In-Hospital Mortality Among 17.804 Patients Swindle JP. Arch Intern Med 2010: 170: 631-637

38. Unresolved Issues in ICD Rx Cardiologist and Electrophysiologist are dealing with pts who have multiple concomitant diseases GLs based on RCT should not be employed w/out first carefully considering all the factors that might influence the treatment decision in an individual pt Comorbid conditions will limit any potential benefit from an ICD implant (avoid risks and costs) This principle should also apply to decision regarding elective ICD generator replacements for battery depletion

39. Potential Barriers ti the Dissemination of ICD Rx Patient level Difficulty understanding risks Concern over the safety of ICD Concern over the impact on QOL Skepticism about the benefit of ICD expecially in the absence of symptoms Personal biases and cultural influences HCP / Institutional level Difficulty identifieng pts Limited stuff capacity Lack of funding for ICD Rx Lack of applicability of RCT Concern over the relative benefit at an individual pts level Concern over the safety of ICD and leads Dissatisfaction with the high rate of inappropriate shock Need for better tools to stratify pts for SCD HCP biases and cultural influences Purchaser / Payer level The cost of ICD Rx The very high numbers of eligible pts fpr primary prevention ICDs

40. How Well Do ICDs Work ? Conclusion ICDs Rx has proved effective in preventing SD Significant barriers to implementation remain with respect to: - identification of pts @ risk - cost of the Rx - acceptance of ICDs by pts and providers Effort should focused to facilitate dissemination of ICD Rx - better tools to risk-stratify pts for SCD - educating pts and HCPs about SCD and ICDs - improving ICD technology to enhance safety and reduce the risk of inappropriate shocks