R Grimm : Speaker - St. Jude, Medtronic, GE Research Grant - GE S Nagueh: Speaker - Medtronic

1. Presenter Disclosure InformationJohn F. Beshai, MDRethinQ Trial ResultsDisclosures Information:The following relationships exist related to this presentation:Consultant - St. Jude Medical, AtricureResearch Grant - St. Jude Medical R Grimm : Speaker - St. Jude, Medtronic, GE Research Grant - GE S Nagueh: Speaker - Medtronic Consultant - St. Jude J Baker : no disclosures S Beau: no disclosures S Greenberg: Consultant - Medtronic, St. Jude, Boston Scientific L Pires: Consultant - St. Jude P Tchou: no disclosures

2. The Resynchronization Therapy in Normal QRS (RethinQ) Study John F. Beshai, MD, Richard A. Grimm, DO, Sherif F. Nagueh, MD, James H. Baker II, MD, Scott L. Beau, MD, Steven M. Greenberg, MD, Luis A. Pires, MD, Patrick J. Tchou, MD for the RethinQ study investigators Study Sponsored by St. Jude Medical

3. Background • Currently, indications for cardiac resynchronization therapy (CRT) include QRS duration > 120ms, LVEF < 35% and NYHA Class III-IV. • 20-30% of patients do not respond to CRT despite application of established selection criteria. • Patients with normal conduction or a slightly prolonged QRS duration also exhibit mechanical abnormalities due to intraventricular dyssynchrony. • Myocardial Tissue Doppler Imaging (TDI) allows both the velocity and timing of regional longitudinal motion to be measured. • LV dyssynchrony may also be useful in predicting the benefit of CRT before implantation of the pulse generator.

4. Hypothesis • We hypothesized that patients with NYHA class III, left ventricular ejection fraction less than or equal to 35%, narrow QRS duration < 130 ms, and evidence of mechanical dyssynchrony on echocardiography may benefit from cardiac resynchronization therapy.

5. Study Design Overall Objective Determine CRT safety and efficacy in patients who are candidates for an ICD with NYHA Class III, narrow QRS duration (<130 ms) and evidence of mechanical dyssynchrony as measured by echocardiography/Tissue Doppler Imaging Primary Endpoint Improvement in Peak VO2 during CPET of at least 1.0ml/kg/min at 6 months. Secondary Endpoints Improvement in quality of life score at 6-months Improvement in NYHA classification at 6-months

6. Inclusion Criteria NYHA class III HF LVEF ≤ 35% Evidence of mechanical dyssynchrony QRS duration < 130ms Exclusion Criteria NYHA class I, II, or IV Permanent Atrial Fibrillation Recent MI, unstable angina or cardiac revascularization Prior cardiac resynchronization therapy Inclusion and Exclusion Criteria

7. Echo Criteria for LV Dyssynchrony Mechanical dyssynchrony considered present if either • M-Mode - Septal posterior wall mechanical delay (SPWMD) ≥ 130 ms OR • Tissue Doppler Imaging (TDI) of the basal ventricular segments in apical 4/2/3 chamber views - Septal to lateral delay ≥ 65ms OR - Antero-septal to posterior delay ≥ 65ms

8. Study Design

9. Results § Includes ARBs and other ACE substitutes, including Hydralazine

10. Baseline Mechanical Dyssynchrony

11. LV end diastolic diameter (mm) LV end systolic diameter (mm) Mean +/- 1 SD Mean +/- 1 SD 80 80 p = 0.29 p = 0.06 60 60 40 40 Control Control CRT CRT 20 n = 87 n = 87 20 n = 85 n = 85 0 0 Baseline Echocardiographic Data

12. Control Control CRT CRT n = 87 n = 87 n = 85 n = 85 LV end diastolic volume (mL) LV end systolic volume (mL) Mean +/- 1 SD Mean +/- 1 SD 300 300 p = 0.61 p = 0.43 200 200 100 100 50 50 0 0 Baseline Echocardiographic Data (Cont)

13. 25 25 15 15 Peak VO2(ml/kg/min) Exercise Duration (min) p = 0.85 p = 0.85 20 20 Mean +/- 1 SD Mean +/- 1 SD 10 10 15 15 10 10 5 5 Control Control CRT CRT 5 5 n = 87 n = 87 n = 85 n = 85 0 0 0 0 Baseline Evaluations

14. Control Control CRT CRT n = 87 n = 87 n = 85 n = 85 100 p = 0.43 400 400 p = 0.95 Quality of Life Score Six-minute Hall Walk Distance (m) 80 Mean +/- 1 SD Mean +/- 1 SD 300 300 60 200 200 40 20 100 100 0 0 0 Baseline Evaluations (Cont)

15. Patient Flow Analysis • 172 patients randomized (87 CRT and 85 control) • 11 patients in CRT group and 5 patients in control group not included in endpoint analysis • < 6 months of follow up (7 patients) • Unable to complete CPET at 6 month visit for reason other than worsening HF (3 patients) • Death not due to worsening HF (3 patients) • Withdrawal prior to 6 month visit (3 patients) • 156 patients (76 CRT and 80 control) were available for efficacy analysis

16. Results - Primary Endpoint Peak VO2 (ml/kg/min) 14 Median & 95% CI 12 10 p = 0.75 8 Baseline 6-months % Improved in Peak VO2 100 p = 0.63 80 46% 41% 60 40 Control (n = 80) CRT (n = 76) Control n = 80 CRT n = 76 20 0

17. 70 p = 0.91 60 Quality of Life Median & 95% CI 50 NYHA Class 40 100 30 p = 0.006 Baseline 6-months 80 64% 60 54% 41% 40 29% 20 8% 5% Control (n = 80) 0 CRT (n = 76) Improved No Change Worsened Control (n = 80) CRT (n = 76) Results - Secondary Endpoints

18. LV Volumes and Dimensions Change in LVEDV/ LVESV Median & 95% CI p = 0.71 p = 0.81 10 0 -20 -40 LVEDV LVESV Control CRT Change in LVEDD/ LVESD Median & 95% CI 4 p = 0.49 p = 0.34 2 0 -2 -4 LVEDD LVESD

19. Peak VO2 by sub-group Peak VO2 (% improved from baseline) Peak VO2 (% improved from baseline) 100 100 p = 0.45 p = 0.02 p = 0.82 p = 0.25 80 80 60 60 40 20 40 Control Control Control Control CRT CRT CRT CRT 0 n = 55 n = 17 n = 59 n = 25 n = 36 n = 40 n = 41 n = 39 20 Ischemic Non-ischemic 0 QRS ≥ 120 ms QRS < 120 ms

20. Summary • This prospective, multi-center, randomized trial was designed to evaluate the effectiveness of CRT therapy in a HF population with narrow QRS duration and evidence of mechanical dyssynchrony. • There was no statistical significant difference in the change in Peak VO2 between the treatment and control group during cardiopulmonary exercise testing. • No improvement in other objective parameters including 6-minute walk test, LV reverse remodeling, and secondary endpoint - quality of life score .

21. Summary • NYHA class improved to a greater extent in the treatment group than in the control group. • Although numbers were small in the sub-group analysis, there was no statistically significant difference in the primary endpoint between ischemic and non-ischemic patients. • Patients with QRS duration 120 - 130 ms demonstrated an improvement in peak VO2.

22. Conclusion • CRT did not improve Peak VO2 during exercise in patients with NYHA Class III heart failure, QRS duration <130ms, EF ≤ 35% and mechanical dyssynchrony as specified in this trial. • While there was a statistically significant improvement of NYHA class, a secondary endpoint, there was no improvement in quality-of-life, 6-minute walking test, or echocardiographic measures of reverse LV remodeling • A subgroup of patients with QRS duration between 120 ms and 130 ms demonstrated an improvement from CRT, however patients with QRS duration < 120 ms did not demonstrate improvement • The subgroup of patients stratified on the basis of cardiomyopathy etiology did not demonstrate an improvement in peak VO2.