1. Effects of selective heart rate reduction with ivabradine on left ventricular remodelling and function: results from the SHIFT echocardiography substudy Systolic Heart failure treatment with the I f inhibitor ivabradine Trial Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com

2. Background  Cardiac remodeling is central to the pathophysiology of heart failure (HF) and is a prognostic factor in patients with HF  Left ventricular (LV) enlargement and reduced ejection fraction are powerful predictors of outcomes in heart failure  Therapeutic effects of drugs and devices on LV remodeling are associated with their longer-term effects on mortality Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com

3. Objective the pre-specified echocardiography substudy Objective of the pre-specified echocardiography substudy To evaluate the effects of the I f inhibitor ivabradine on LV remodeling and function:  Primary endpoint: the change in the LV end-systolic volume index (LVESVI) from baseline to 8 months  Secondary endpoints: changes during the same interval in  LV end-diastolic volume index (LVEDVI)  LV end-systolic, end-diastolic volumes (LVESV, LVEDV)  LV ejection fraction (LVEF) Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com

4. Sub-study population Excluded (N=96) 52: Poor quality of echo recording 19: No baseline and/or 8-month recording 8: Non-matching biplane or 4- chamber views 13: Withdrawn due to death 4: Consent withdrawn Excluded (N=104) 203 patients Placebo 208 patients Ivabradine Median follow-up after 8-month echocardiogram: 16.1 months 52: Poor quality of echo recording 15: No baseline and/or 8- month recording 1: Non-matching biplane or 4- chamber views 23: Withdrawn due to death 13: Consent withdrawn 611 patients included from 89 centers in 21 countries 611 patients included from 89 centers in 21 countries 304 patients Ivabradine 307 patients Placebo Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com

5. Baseline characteristics IvabradineN=304PlaceboN=307 Mean age, years Mean age, years6059 Male, % Male, %8082 Mean BMI, kg/m 2 Mean BMI, kg/m 22828 Mean HF duration, years Mean HF duration, years44 HF ischaemic cause, % HF ischaemic cause, %6765 NYHA class II, % NYHA class II, %4846 NYHA class III, % NYHA class III, %5153 Mean LVEF, % Mean LVEF, %3232 Mean HR, bpm Mean HR, bpm7879 Mean systolic BP, mm Hg Mean systolic BP, mm Hg121119 Mean diastolic BP, mm Hg Mean diastolic BP, mm Hg7575 Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com

6. Baseline background treatment IvabradineN=304PlaceboN=307 Beta-blocker, % Beta-blocker, %92 ACE inhibitor, % ACE inhibitor, %8083 ARB, % ARB, %1712 Diuretic (excludes antialdo), % Diuretic (excludes antialdo), %87 Aldosterone antagonist, % Aldosterone antagonist, %7471 Digitalis, % Digitalis, %2732 Devices, % Devices, % 3 4 Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com

7. LVESVI > 59 mL/m 2 LVESVI < 59 mL/m 2 HR 1.62, p=0.04 LV end-systolic volume index and outcome in the placebo group Patients with primary composite endpoint, % Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com 60 40 20

8. Primary endpoint: change in LVESVI from baseline to 8 months 0 50 75 70 65 60 55 mL/m 2 65.2±29.1 58.2±28.3 63.6 ±30.1 62.8 ±28.7 7.0 ± 16.3  - 7.0 ± 16.3 - 0.9 ± 17.1  - 0.9 ± 17.1 ∆ -5.8, P<0.001 Left ventricular end-systolic volume index Ivabradine (n=208)Placebo (n=203) Baseline 8 months Baseline 8 months Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com

9. Secondary endpoint: change in LVEDVI from baseline to 8 months 0 75 100 95 90 85 80 mL/m 2 93.9 ±32.885.9 ±30.9 90.8 ±33.189.0±31.6 -7.9 ± 18.9  -7.9 ± 18.9 -1.8 ± 19.0  -1.8 ± 19.0 Ivabradine (n=204)Placebo (n=199) Baseline 8 months Baseline 8 months ∆ -5.5, P=0.002 Left ventricular end-diastolic volume index Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com

10. Baseline M008 Secondary endpoint: change in LVEF from baseline to 8 months 65.2 ± 29.1 0 5 10 15 20 25 30 35 40 % 32.3±9.1 34.7±10.2 31.6 ±9.3 31.5±10.0 2.4 ± 7.7  2.4 ± 7.7 - 0.1 ± 8.0  - 0.1 ± 8.0 Ivabradine (n=204)Placebo (n=199) Baseline 8 months Baseline 8 months ∆ + 2.7, P<0.001 Left ventricular ejection fraction Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com

11. Summary of changes in HR, LV end- systolic/end-diastolic volume indexes Ivabradinen=304Placebon=307P Change in resting HR at 8 months, bpm - 14.7- 5.8<0.001 Change in LVESVI at 8 month, mL/m 2 - 7.0- 0.9<0.001 Change in LVEDVI at 8 month, mL/m 2 - 7.9- 1.80.002 Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com

12.  Heart rate reduction with ivabradine reverses left ventricular remodeling in patients with heart failure and LV systolic dysfunction:  Marked reductions of LV volumes  Significant improvement of LV ejection fraction  These results suggest that ivabradine modifies disease progression in patients with HF receiving background therapy Conclusions Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com