1. REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction: Results of the REVERSE Trial Cecilia Linde, Stockholm, Sweden William T. Abraham, Columbus, U.S Michael R. Gold, Charleston, U.S. Jean-Claude Daubert, Rennes, France On Behalf of the REVERSE Investigators and Coordinators

2. Acknowledgments Steering Committee W. T. Abraham, J-C. Daubert (study initiator), M. Gold, C. Linde (coordinating clinical Investigator) Echo Core Labs Ghio, S, St. John Sutton, MG Adverse Events Advisory Committee D. Böcker, J. P. Boehmer, J. G. F. Cleland, M. Gold, J. T. Heywood, A. Miller (chair) Data Monitoring Committee J. Aranda, J. Cohn (chair), P. Grambsch; M. KomajdaInvestigators Austria: H. Mayr, A. Teubl; Belgium: R. Willems; Canada: C. Simpson; Czech Republic: J. Lukl; Denmark: H. Eiskjær, C. Hassager, M. Møller, T. Vesterlund; France: E. Aliot, P. Chevalier, J-C. Daubert, J-M. Davy, P. Djiane, H. Le Marec; Germany: G. Groth, G. Klein, T. Lawo, C. Reithmann; Hungary: T. Forster, T. Szili-Török; Ireland: R. Sheahan; Italy: S. Lombroso, M. Lunati, L. Padeletti, M. Santini; Netherlands: B. Dijkman; Norway: S. Færestrand, F. T. Gjestvang; Spain: I. Fernandez Lozano, R. Muñoz Aguilera, A. Quesada Dorador; Sweden: C. Linde, F. Maru, K. Säfström; United Kingdom: G. Goode; United States: U. Birgersdotter-Green, J. Boehmer, E. Chung, S. Compton, J. Dinerman, D. Feldman, R. Fishel, G. J. Gallinghouse, M. Gold, S. Hankins, J. Herre, M. Hess, E. Horn, S. Hsu, S. Hustead, S. Jennison, E. Johnson, W. B. Johnson, G. Jones, R. Malik, A. Merliss, S. Mester, S. Moore, N. Nasir, F. Pelosi, Jr., D. Renlund, K. Rist, R. Sangrigoli, R. Silverman, D. Smull, K. Stein, L. Stevenson, J. Stone, N. Sweitzer, D. Venesy, L. Zaman.Sponsor Medtronic Inc.

3. Primary Obj: composite (mortality, HF hospitalization, and VT/VF) 2004: MICD II 6 months, n=186 Primary Obj: Peak V02 Primary Obj: Packer’s HF Clinical Composite Primary Obj: mortality or HF events (i.e. HF hosp or IV therapy) 2008: REVERSE 12 months, n=610 2003: Contak CD 6 months, n =263 2010: MADIT CRT Approx. 33 months, n=1820 2010: RAFT Minimum 18 months, n=1800 Primary Obj: composite (total mortality and HF hospitalization) Landscape of CRT Trials in NYHA I, II

4. To determine the effects of CRT with or without an ICD on disease progression over 12 months in patients with asymptomatic and mildly symptomatic heart failure and ventricular dysynchrony Randomized, double-blind, parallel-controlled clinical trial REVERSE Purpose and Design

5. NYHA Class II or I (previously symptomatic) QRS  120 ms; LVEF  40%; LVEDD  55 mm Optimal medical therapy (OMT) Without permanent cardiac pacing With or without an ICD indication Inclusion Criteria

6. Baseline Assessment Successful CRT Implant Randomized 1:2 CRT OFF (OMT ± ICD) CRT ON (OMT ± ICD) U.S., Canada: at 12 Months, all patients recommended CRT ON Europe: remain in randomization assignment for 24 Months, all patients recommended CRT ON at 24 months All Geographies: Follow-up 5 years 1 2 12 Months Study Schematic

7. Primary: HF Clinical Composite Response, comparing the proportion of patients worsened in CRT OFF vs. CRT ON groups Composite includes: all-cause mortality, HF hospitalizations, crossover due to worsening HF, NYHA class, and the patient global assessment assessed in double blind manner Prospectively Powered Secondary: Left Ventricular End Systolic Volume Index (LVESVi) comparing CRT OFF vs. CRT ON subjects LVESVi is assessed by two core labs (1 in Europe, 1 in U.S) End Points

8. 684 Enrolled (2004-2006) 642 Implant Attempts 610 Patients Randomized U.S. 343 (56%); Europe 262 (43%); Canada 5 (<1%) CRT OFF 191 PatientsCRT ON 419 Patients - 594/598 completed 12 month follow-up - 12 deaths - 0 lost to follow-up, 0 exits -21 unsuccessful implants 621 Successful CRT Implants (97%) - 42 ineligible or withdrew -11 exits after successful implant Enrollment and Randomization

9. CRT OFF N=191 CRT ON N=419 P-value Age (mean) 61.8 ± 11.662.9 ± 10.60.26 NYHA II (%) 83%82%0.82 ICD (%) 85%82%0.41 Beta-blockers94% 96%0.32 ACE-i/ ARB 97% 96%0.63 Diuretics 77% 81%0.33 EF (%)26.4 ± 7.026.8 ± 7.00.50 LVEDD (mm)70 ± 9 69 ± 90.34 QRS (ms)154.4 ± 24.1152.8 ± 21.00.41 Ischemic51% 56%0.22 Baseline Characteristics (n=610)

10. CRT OFF N=191 CRT ON N=419 P-value BMI kg/m 2 28.3290.11 Systolic BP mmHg Systolic BP mmHg 1251230.25 Diastolic BP mmHg 72.272.00.82 Female22.0%20.4%0.75 LBBB76.6%78.0%0.76 1st degree AV block 19.1%20.9%0.59 6-min walk distance (m) 3864030.34 MN LWHF QOL score (0-105) 29.126.90.32 KCCQ QOL score (0-100) 70.873.80.14 Baseline Characteristics (n=610)

11. Improved / Unchanged Pre-Specified Analysis Proportion Worsened Primary End Point: Clinical Composite Response 79% 84% 16% 21% 0% 20% 40% 60% 80% 100% CRT OFFCRT ON P=0.10 Worsened

12. 40% 54% 39% 30% 16% 21% 0% 20% 40% 60% 80% 100% CRT OFFCRT ON Improved / Unchanged Pre-Specified Analysis Proportion Worsened Conventional Analysis Distribution Worsened/Unchanged /Improved Worsened Unchanged Improved P=0.004 Primary End Point: Clinical Composite Response 79% 84% 16% 21% 0% 20% 40% 60% 80% 100% CRT OFFCRT ON P=0.10 Worsened

13. Clinical Composite Response CRT OFF (n=191) CRT ON (n=419) WORSENED41 (21%)67 (16%) Death3 (2%)9 (2%) Hosp. For worsening HF14 (7%)12 (3%) Crossover due to worsening HF5 (3%)1 (<1%) Worsened Patient Global Assessment and NYHA0 (0%)2 (<1%) Worsened NYHA Only18 (9%)40 (10%) Worsened Patient Global Assessment Only1 (1%)3 (1%) IMPROVED76 (40%)228 (54%) Improved on Patient Global Assessment and NYHA11 (6%)69 (16%) Improved NYHA Only28 (15%)59 (14%) Improved Patient Global Assessment Only37 (19%)100 (24%) UNCHANGED74 (39%)124 (30%) Note: Data in table is listed in hierarchical order (subjects are included only in one sub-category) Clinical Composite Response Details

14. 70 75 80 85 90 95 100 105 110 115 Baseline12 Months LVESVi (ml/m 2 ) CRT OFF  = -1.3 CRT ON  = -18.4 P<0.0001 n=487 Powered Secondary End Point: LVESVi (ml/m 2 )

15. 12 MonthsBaseline (ml/m 2 ) LVEDVi (ml/m 2 ) P<0.0001 LVEF (%) P<0.0001 12 MonthsBaseline CRT OFF ∆ = 0.6 CRT ON ∆ = 3.8 CRT OFF ∆ = -1.4 CRT ON ∆ = -20.5 n=487 20 22 24 26 28 30 32 34 90 100 110 120 130 140 150 Other Remodeling Parameters

16. % of Patients Hospitalized for HF Number at Risk CRT OFF 191 187 181 176 119 CRT ON 419 415 411 409 251 P=0.03 Hazard Ratio=0.47 CRT OFF CRT ON Months Since Randomization Time to First HF Hospitalization

17. MN LWHF P=0.26 6-Min Walk Test P=0.26 Other Secondary End Points: QOL, 6MHW

18. P=0.06 Other Secondary End Points: NYHA

19. 97% implant success rate 9.5 % LV-lead related complications 66 in 59 / 621 successfully implanted patients LV lead dislodgements, diaphragmatic stimulation, subclavian vein thrombosis, etc. Safety

20. REVERSE is the first large, randomized, double-blind study to show that CRT in asymptomatic and mildly symptomatic heart failure patients on optimal medical therapy: Reverses LV remodeling Reduces the risk of heart failure hospitalization May improve clinical outcome as assessed by the clinical composite response measure Note: FDA has not yet reviewed the clinical data to determine whether or not CRT systems are safe and effective in this patient population. Conclusion