MADIT Randomized Trial to Reduce Inappropriate Therapy (MADIT-RIT) Arthur J. Moss, MD for the MADIT-RIT Executive Committee AHA Late Breaking Trials November 6, 2012 Los Angles, CA

DISCLOSURE INFORMATION Arthur J. Moss, MD CompanyRelationship Boston Scientific Research Grant Hold no stock or stock options in any device company. Not a member of any corporate advisory group or speakers’ bureau.

MADIT-RIT: BACKGROUND ICD is highly effective in reducing mortality in high-risk cardiac pts. Despite sophisticated device-detection algorithms, 8-40% of ICD therapies are inappropriate with adverse side effects Question: can ICD devices be reprogrammed to safely reduce inappropriate therapies?

MADIT-RIT: Hypothesis Hypothesis Dual-chamber ICD or CRT-D devices with: - high-rate cutoff (>200bpm), or - duration-delay (initial 60sec monitoring plus rhythm ID detection will be associated with fewer 1 st inappropriate therapies than standard/conventional programming (2.5sec >170bpm) without increase in mortality Randomized, 3-arm study using Boston Scientific devices

Randomization Arms Arm A (Conventional) Arm B (High-rate) Arm C (Duration-delay) Zone 1: >170 bpm, 2.5s delay 170 bpm >170 bpm, 60s delay Onset/Stability Detection Enhancements ON Monitor onlyRhythm ID Detection Enhancements ON ATP + Shock Zone 2: >200 bpm, 1s delay>200 bpm, 2.5s delay>200 bpm, 12s delay Quick Convert ATP Shock Quick Convert ATP Shock Rhythm ID Detection Enhancements ON ATP + Shock Zone 3 : >250 bpm, 2.5s delay Quick Convert ATP + Shock * All programming is within approved labeling MADIT-RIT: Three Treatment Arms*

MADIT-RIT: ELIGIBILITY Inclusion Criteria - I 0 prevention patients with no Hx of VT/VF - Sinus rhythm at enrollment; Hx PAF ok - Pt. on stable, optimal pharmacologic therapy - Age >21 yrs; informed consent Exclusion Criteria - Pt. with pacemaker, ICD or CRT-D device - CABG or PTCA in past 3 months - MI (enzyme +) or AF in past 3 months - 2 nd or 3 rd degree heart block - NYHA IV - Chronic AF - Renal disease:BUN>50mg/dlor Creatinine>2.5mg/dL

MADIT-RIT Primary Endpoint PRIMARY (90% power for hazard ratio 0.5 at p<0.05) First episode of inappropriate therapy - B arm vs. A arm - C arm vs. A arm Rationale for first inappropriate therapy (IT) - Expect reprogramming to be common after IT - Protocol allows reprogramming after IT SECONDARY All-cause mortality Syncope MADIT-RIT: Prespecified End Points

MADIT-RIT: POPULATION 1,500 pts. enrolled from 98 centers in US, Canada, Europe, Israel & Japan Average follow-up = 1.4 years

Baseline Demographic and Clinical Characteristics (no significant differences in 22 variables among the 3 Rx groups) VariableTherapy Group ABC Conventional High-rate Duration-delay >170bpm >200bpm>170bpm (n=514) (n=500) (n=486) Age, yrs Male, % Ischemic, % EF, %

Cumulative Probability of First Inappropriate Therapy by Treatment Group

Figure 2. Cumulative Probability of Death by Treatment Group

Treatment Groups Treatment Group Comparisons Events# of patients B vs. AC vs. A A B C Hazard RatioP-value Hazard RatioP-value n=514 n=500 n=486 First Inappropriate Rx < <0.001 Death 1 st Syncope FREQUENCY AND HAZARD RATIOS FOR INAPPROPRIATE THERAPY, DEATH, AND SYNCOPE BY TREATMENT GROUP

Arrhythmias Triggering First Inappropriate Therapies Treatment Group A B C Arrhythmias (# Pts. 1 st Inapp. Therapies) At Fib/Flut Regular SVT Other Note: marked reduction in patients with1 st inappropriate therapies in High-rate (B) and Duration-delay (C) groups for At Fib/Flut and Regular SVT when compared to Conventional therapy (A).

Treatment Group P-value A B C B v A C v A n=514 n=500 n=486 no. of patients (% of Rx group) Any Appropriate Therapy Shock 28 (5) 26 (5) 19 (4) ATP 111 (22) 38 (8) 20 (4) <0.001 <0.001 Any Inappropriate Therapy Shock 31 (6) 14 (3) 15 (3) ATP 104 (20) 20 (4) 25 (5) <0.001 <0.001 Any Appropriate and Inappropriate Therapy by Treatment Group

MADIT-RIT: CONCLUSIONS Improved ICD programming at high-rate (>200 bpm) or 60sec duration-delay is associated with: 1) ~75% reduction in 1 st inappropriate therapy; 2) ~50% reduction in all-cause mortality We believe the decrease in mortality is related to the reduction in adverse inappropriate shock and ATP therapies.

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