Magnitude of SCD in the US

Reducing Risk of Sudden Death Mehmet K. Aktaș, MD Magnitude of SCD in the US Stroke 3 Lung Cancer 2 167,366 157,400 SCD claims more lives each year than these other diseases combined 450,000 SCD 4 Breast Cancer 2 AIDS 1 40,600 42,156 #1 Killer in the U.S. 1 U.S. Census Bureau, Statistical Abstract of the United States: 2001. 2 American Cancer Society, Inc., Surveillance Research, Cancer Facts and Figures 2001. 3 2002 Heart and Stroke Statistical Update, American Heart Association. 4 Circulation. 2001;104:2158-2163. 1

SCD Resuscitation Success versus Time* 100 90 80 Chance of success reduced 7-10% each minute 70 % Success *Non-linear 60 50 40 30 20 10 0 1 2 3 4 5 6 7 8 9 Time (minutes) Cummins RO. Ann Emerg Med. 1989;18:1269-1275. SCD Chain of Survival Statistics Even in the best EMS/early defibrillation programs it is difficult to achieve high survival rates 48-58% SCD events are not witnessed 1,2 85% SCD events occur at home/non-public locations 1 4.6-8% estimated SCD out-of-hospital survival 1,2 1 Nichol G, et al. JAMA. 2008;300:1423-1431. 2 Chugh SS, et al. J Am Coll Cardiol. 2004;44:1268-1275. 2

Risk Factors Prior heart disease is a major risk factor for cardiac arrest Patients with prior MI and those with HF are at highest risk Congenital heart disease HCM and ARVD Fonorow GC. Epidemiology and risk stratification in acute heart failure. JAMA 2005;293:572 ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults Myocardial Substrate Abnormalities Loss of myocytes Changes in cell cell communication Discontinuous electrical propagation Reentrant circuit 3

Risk of Sudden Death in HF Control Group Mortality % 45 months 13 months 41.4 months 27 months 12 months 16 months 6 months Total Mortality ~15% to 40% SCD Accounts for ~50% of Total Deaths Severity of Heart Failure & Modes of Death NYHA II 12% 24% 64% CHF Other Sudden Death n = 103 NYHA III 26% 59% 15% CHF Other Sudden Death NYHA IV CHF n = 103 33% 56% Other 11% Sudden Death n = 27 MERIT-HF Study Group. Effect of Metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). LANCET. 1999;353:2001-07. 4

Electrophysiologic Disorders Long QT syndrome WPW-Wolff-Parkinson-White Brugada syndrome CPVT-Catecholaminergic Polymorphic VT ARVD- Arrhythmogenic Right Ventricular Dysplasia HCM- Hypertrophic Cardiomyopathy Short QT syndrome Identification of At-Risk Patients History Syncope, Seizures, Aborted Cardiac Arrest Circumstances: rest vs exertion Onset: gradual vs sudden Family History Premature sudden death Drownings ECG Genetic Testing Sudden death panel 10 5

Sinai Hospital of Baltimore recruited Dr. Mirowski and offered him opportunity to work on ICD idea Mirowski and Martin Mower developed protypes in the research lab In 1969, experimental model First transvenous defibrillation (1969) Canine implants (1970s), First human implant: 1980 (Johns Hopkins, Baltimore) ICD Development 6

Defibrillation Through A Single Intravascular Catheter 7

Fib-Defib in Active Conscious Dogs Circ 58:90-94, 1978. 8

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MADIT II Survival Results 1.0 Probability of Survival 0.9 0.8 0.7 Conventional Defibrillator 54% Reduction 0.6 P = 0.007 0.0 0 1 2 3 4 No. At Risk Year Defibrillator 742 502 (0.91) 274 (0.94) 110 (0.78) 9 Conventional 490 329 (0.90) 170 (0.78) 65 (0.69) 3 MADIT II: Mortality Events 31% relative risk reduction 61% relative risk reduction 10

MADIT II Subgroup Analyses There were no statistically significant interactions in the various subgroups. Note the overlapping error bars. 11

SCD HeFT Protocol DCM + CAD and CHF EF < 35% NYHA Class II or III 6-Minute Walk, Holter R 2521 Patients Placebo N = 847 Amiodarone N = 845 ICD Implant N = 829 Minimum of 2.5 years follow-up required 45 months average follow-up Optimized B, ACE-I, Diuretics SCD HeFT Mortality Rate Overall Results 0.4 Hazard Ratio (97.5% Cl) P-Value Amiodarone vs. Placebo 1.06 (0.86-1.30) 0.53 ICD vs. Placebo 0.77 (0.62-0.96) 0.007 0.3 Mortality Rate 0.2 0.1 0.0 0 12 No. at Risk Months of Follow-Up Amiodarone 845 772 715 484 280 97 Placebo 847 797 724 505 304 89 ICD 829 778 733 501 304 103 24 36 Amiodarone Placebo ICD 48 60 12

Results from Primary and Secondary ICD Prevention Trials MADIT I 1996 AVID 1997 CABG Patch 1997 CASH* 2000 CIDS 2000 MADIT II 2002 DEFINITE 2004 DINAMIT 2004 Trial Name, Pub Year 0.46 N = 196 0.62 0.69 N = 1016 N = 458 0.65 0.83 0.82 N = 1232 SCD HeFT N = 1676 2005 0.77 Hazard ratio N = 191 N = 659 N = 900 1.07 1.08 N = 674 LVEF, other features 35 or less, NSVT, EP positive Aborted cardiac arrest 35 or less, abnormal SAECG and scheduled for CABG Aborted cardiac arrest Aborted cardiac arrest or syncope 30 or less, prior MI 35 or less, NICM and PVCs or NSVT 35 or less, MI within 6 to 40 days and impaired cardiac autonomic function 35 or less, LVD due to prior MI and NICM 0.4 0.6 0.8 1.0 1.2 1.4 ICD better 1.6 1.8 S-ICD System Protection without touching the heart 13

S-ICD System Highlights Completely subcutaneous Does not require leads in the heart, leaving the vasculature untouched 80 J (delivered) biphasic shock 5.1 year longevity S-ICD Device Placement 14

Implantable Cardioverter-Defibrillators I IIa IIb III I IIa IIb III I IIa IIb III ICD therapy is indicated in patients who are survivors of cardiac arrest due to ventricular fibrillation or hemodynamically unstable sustained VT after evaluation to define the cause of the event and to exclude any completely reversible causes. ICD therapy is indicated in patients with structural heart disease and spontaneous sustained VT, whether hemodynamically stable or unstable. ICD therapy is indicated in patients with syncope of undetermined origin with clinically relevant, hemodynamically significant sustained VT or VF induced at electrophysiological study. All primary SCD prevention ICD recommendations apply only to patients who are receiving optimal medical therapy and have reasonable expectation of survival with good functional capacity for more than 1 year. Implantable Cardioverter-Defibrillators I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III ICD therapy is indicated in patients with LVEF less than or equal to 35% due to prior MI who are at least 40 days post-mi and are in NYHA functional Class II or III. ICD therapy is indicated in patients with nonischemic DCM who have an LVEF less than or equal to 35% and who are in NYHA functional Class II or III. ICD therapy is indicated in patients with LV dysfunction due to prior MI who are at least 40 days post-mi, have an LVEF less than or equal to 30%, and are in NYHA functional Class I. ICD therapy is indicated in patients with nonsustained VT due to prior MI, LVEF less than or equal to 40%, and inducible VF or sustained VT at electrophysiological study. All primary SCD prevention ICD recommendations apply only to patients who are receiving optimal medical therapy and have reasonable expectation of survival with good functional capacity for more than 1 year. 15

Wearable Cardioverter-Defibrillator ECG Electrodes Dry & nonadhesive 4 electrodes providing 2 channels of monitoring Self-Gelling Defibrillation Electrodes Response Buttons Monitor 150 joules biphasic Stores ECG, daily use, etc. LifeVest Electrodes ECG Electrode Defibrillation Electrode Gel Capsules 16

Alarm Sequence 1. Arrhythmia detected, activating vibration alert 2. Siren alerts begin 3. Siren alerts get louder 4. Patient audible prompt: Electrical shock possible. 5. Gel release 6. Bystander audible prompt: "Do not touch patient. 7. Treatment shock delivered. Who Qualifies Primary prevention & LVEF 35% Post-MI Coverage during the 40 day ICD waiting period Pre/Post Revascularization Coverage during the 90 day ICD waiting period Listed for cardiac transplant New NICM Coverage during the 3 to 9 month ICD waiting period NYHA class IV heart failure Terminal disease with life expectancy of less than 1 year ICD explantation 17

URMC Case 1 60 yo woman with recurrent PVC s s/p PVC ablation Holter showed NSVT LifeVest ordered prior to discharge 18

URMC Case 2 63 year old man with CAD and ICM Had ICD implanted but required extraction due device infection Patient discharged home with IV antibiotics and LifeVest 19

3/20/2015 URMC Case 3 48 year old man with newly diagnosed NICM Cardiac sarcoid Patient started on appropriate meds Discharged with LifeVest Received appropriate therapy 3 weeks later 20

Medical Orders Cumulative Life-Vest by the Numbers >60,000 patients have worn LifeVest 98% first shock efficacy 92% shocked event survival (conscious ER arrival or stayed at home) Average use: 2-3 months Median daily use is 94% (22.5 hours/day) 21

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