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

15 min

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

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:

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 ( ) The long-term benefit was also evident in an ITT analysis. P= FU 20 ms 0,17 LYS AR = 6% NNT = 17

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: modif. ICD Therapy Drug Therapy

CABG (Chronic CAD, mild angina, 3 VD) Hypertension therapy (Diastolic 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

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)

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

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= Hernandez JAMA 2007; 298: Less than 40% of potentially eligible pts hospitalized for HF received ICD Rx. Rate of use were lower among women and black patients

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

Merkely B. EUROPACE 2010

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

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

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

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 …

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

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

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

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, SA-ECG988319,34, SVA956413,44, HRV571925,85, EPS402225,53,96.68,.5 Bailey JJ. J Am Coll Cardiol 2001; 38: modif. MTWA 17,8 3,8 Reduced EF is single most important RF for overall mortality and SD

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

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

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

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:

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

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

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

Risk Stratification in MADIT-II Predictors of Long-Term Mortality (655 pts – 9-year follow-up) VariablesHR95% CIP value Diabetes AF (Non SR) Age > <0.001 NHYA > II <0.001 BUN > 28 mg/dl <0.001 Cygankiewicz I. Heart Rhythm 2009: 6:

ICER of ICD Tx by Age Subgroup Chan PS. Circ Cardiovasc Qual Outcomes 2009; 2: 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

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

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

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

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

Bai R. – Natale A. J Cardiovasc Electrophysiol 2008; 19: 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

Acute Device Complications Among Patients Swindle JP. Arch Intern Med 2010: 170:

In-Hospital Mortality Among Patients Swindle JP. Arch Intern Med 2010: 170:

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

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

How Well Do ICDs Work ? Conclusion ICDs Rx has proved effective in preventing SD Significant barriers to implementation remain with respect to: - identification of 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