Anne B. Curtis, Buffalo, NY Seth J. Worley, Lancaster, PA Philip B. Adamson, Oklahoma City, OK

1. BLOCK HF StudyBiventricular versus Right Ventricular Pacing in Patients with Left Ventricular Dysfunction and Atrioventricular Block – Preliminary Results Anne B. Curtis, Buffalo, NY Seth J. Worley, Lancaster, PA Philip B. Adamson, Oklahoma City, OK Eugene S. Chung, Cincinnati, Ohio Imran Niazi, Milwaukee, WI Lou Sherfesee, Minneapolis, MN Timothy S. Shinn, Ann Arbor, MI Martin St. John Sutton, Philadelphia, PA On behalf of the BLOCK HF Trial Investigators and Coordinators

2. Acknowledgments Steering Committee Curtis AB (Principal Investigator), Adamson PB , Chung ES, St. John Sutton MG, Worley SJ Echo Core Lab St. John Sutton MG, Plappert T Adverse Events Advisory Committee Boehmer JP, Meyer TE(Chair), Smith AL, De LurgioDB Data Monitoring Committee Steinberg JS (Chair), DeMarco T, Elkayam U, Louis TA (Statistician) Investigators Canada: RinneC, ThibaultB United States: Adamson PB, Al-Sheikh T, Andriulli J, Barber MJ, Beau S, Bell M, Borgatta L, Brodine W, Canosa R, Chung ES, Compton S, Curtis AB, Ellison K, Evonich R, Faddis M, Foreman B, Murray C, Guerrero M, Herre J, Hodgkin D, Huang D, Keim S, Kocovic D, Kusmirek SL, LessmeierT, Levanovich P, Lobban JH, Mackall JA, Manaris A, McBride W, McKenzie J, MelaT, Merliss A, Mitrani R, Mittal S, Mounsey P, Navone A, Niazi I, Obel O, Oren J, Patel P, Patel V, Pickett A, Rao A, Rist K, Rosenblum A, Saba S, Sakaguchi S, Sandler D, Sangrigoli R, Shinn TS, Simmons T, Simonson J, Smith JE, Telfer EA, Tobias S, Tomassoni G, Worley SJ Sponsor Medtronic Inc. Clinical Trials.gov Identifier: NCT00267098 Caution: Use of CRT devices for AV block and systolic dysfunction patients without ventricular dyssynchrony is not an approved use in the United States. BLOCK HF

3. Background • Clinical Importance • Approximately 1 million people in the US have atrioventricular (AV) block • Currently treated with standard pacemaker (i.e. right ventricular (RV pacing)) therapy • Approximately 6 million in the US are currently diagnosed with heart failure (HF) and approximately 670,000 new cases confirmed each year • According to AHA 2012 statistics, this costs the US approximately $20 to $56 billion annually • DAVID and MOST Trial results have shown that RV pacing may have long-term deleterious effects • Can biventricular (BiV) pacing prevent progression of heart failure and its clinical and economic consequences in AV block? BLOCK HF

4. Study Design • ELIGIBILITY CRITERIA • AV block necessitating pacing • Left ventricular ejection fraction (LVEF) < 50% • NYHA functional class I, II or III • Absence of a Class I indication for resynchronization therapy • No previous pacemaker or implantable cardioverter defibrillator (ICD) • Echocardiography performed at Randomization, 6, 12, 18 and 24 months Implant (CRT-P/D) Establish OMT (30-60 days) Randomize 1:1 Control: RV pacing Treatment: BiV pacing Double-Blind OMT=optimal medical therapy CRT-P=cardiac resynchronization therapy pacemaker CRT-D=CRT defibrillator Follow-up Every 3 months Follow-up Every 3 months BLOCK HF

5. Study Purpose and Objectives • Purpose:Biventricular pacing is superior to RV apical pacing in patients with AV block and LVEF <50% who require ventricular pacing • Endpoints: • Primary:Composite of: • All-cause mortality, • HF-related urgent care, defined as • HF hospitalization requiring IV therapy, or • Any unplanned visit requiring intravenous HF therapy, and • Increase in left ventricular end systolic volume index (LVESVI) >15% • Key Secondary: All-cause mortality, • All-cause mortality/HF hospitalization, • HF hospitalization BLOCK HF

6. Methods • Study featured: • Adaptive sample size • Pre-specified interim analyses • Stopping rules for success, safety, futility • Analysis: Intention-to-treat Bayesian survival analysis using time to first event • Parameter of interest for each endpoint: BiV to RV hazard ratio (HR) • Metric: Probability that HR < 1 BLOCK HF

7. Study Flow Diagram Enrollment • 227 Subjects not randomized: • 95 Subjects for whom inclusion criteria not met (e.g., AV conduction testing criteria not met prior to implant) • 14 Subject withdrawals prior to implant • 51 Unsuccessful implants • 67 Implanted subjects not randomized 918 Assessed for eligibility 691 Randomized 1:1 Allocation • 349 Allocated to Biventricular Pacing • 346 Received allocated intervention • 3 Did not receive allocated intervention • 342 Allocated to Right Ventricular Pacing • 342 Received allocated intervention Follow-up 52 Exited/lost to follow-up 75 Deaths 13 Crossed over to Right Ventricular Pacing 3 Met primary endpoint prior to crossover 50 Exited/lost to follow-up 90 Deaths 84 Crossed over to Biventricular Pacing 50 Met primary endpoint prior to crossover Analysis 349 Analyzed 83 Censored for primary endpoint due to missing LVESVI data 342 Analyzed 71 Censored for primary endpoint due to missing LVESVI data BLOCK HF

8. Follow-Up Experience BLOCK HF

9. Baseline Demographics BLOCK HF

10. Primary Endpoint Results: Mortality/HF Urgent Care/LVESVI BLOCK HF

11. Clinical Components of Primary Endpoint: Mortality/HF Urgent Care Visits BLOCK HF

12. Secondary Endpoint: Mortality/HF Hospitalization BLOCK HF

13. Secondary Objective Results: HF Hospitalization and Mortality HF Hospitalization Mortality BLOCK HF

14. Adverse Events • Note: Table below includes pre-randomization AE’s * Subcategories for other system-related complications such as RA or RV-related complications not included BLOCK HF

15. Strengths and Limitations • Strengths: • Prospective, randomized, double-blind control design • Largest, longest follow-up trial to date • First to show difference in outcomes in AV block and LV systolic dysfunction patients with BiV vs. RV pacing • LIMItations: • Long enrollment duration • Censoring due to missing LVESVI in primary objective • Crossover imbalance between arms: • 24.6% crossed over from RV to BiV • 4.6% crossed over from BiV to RV BLOCK HF

16. Conclusions • In patients with AV block and LV systolic dysfunction (LVEF < 50%), BiV pacing compared to RV pacing leads to a significant 26% reduction in the combined endpoint of mortality, heart-failure related urgent care, and increase in LVESVI. • Furthermore, there is a 27% relative risk reduction in the composite endpoint of heart-failure urgent care and all-cause mortality. BLOCK HF