1. www.shift-study.com S ystolic H eart failure treatment with the I f inhibitor ivabradine T rial Objective, design and baseline www.shift-study.com Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81 Swedberg K, et al. Lancet. 2010;376(9744):875-885

2. www.shift-study.com Primary objective To evaluate whether the I f inhibitor ivabradine improves cardiovascular outcomes in patients with 1. Moderate to severe chronic heart failure 1. Moderate to severe chronic heart failure 2. Left ventricular ejection fraction  35% 2. Left ventricular ejection fraction  35% 3. Heart rate  70 bpm in sinus rhythm 3. Heart rate  70 bpm in sinus rhythm 4. Best recommended therapy 4. Best recommended therapy Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81 www.shift-study.com

3. Study organisation Steering Committee Argentina: S. Perrone Australia: H. Krum Belgium: W. Van Mieghem Brazil: E. Bocchi Bulgaria: T. Katova Canada: P. Liu Chile: J. Jalil China: D. Hu Czech Republic: J. Vitovec Denmark: L. Køber Estonia: T. Uuetoa Finland: M. Niemelä France: G. Jondeau Germany: K. Werdan Greece: D. Kremastinos Hong-Kong: C. Yu Hungary: K. Tóth India: D. S. Rao Ireland: K. Mc Donald Italy: M. Metra Latvia: J. Jirgenson † A. Erglis A. Erglis Lithuania: A. Kavoliuniene Malaysia: K. Sim The Netherlands: A. Voors Norway: K. Dickstein Poland: G. Opolski Portugal: L. Providência Romania: D. Ionescu Russia: G. Aroutiounov Slovakia: R. Hatala Slovenia: M. Sebestjen South Korea: B. Oh Spain: F. Avilés Sweden: R. Willenheimer Turkey: A. Oto United Kingdom: M. Cowie Ukraine: O. Parkhomenko Executive Committee M. Komajda co-chair, K. Swedberg co-chair M. Böhm, J. Borer, I. Ford, L. Tavazzi

4. www.shift-study.com Europe Austria Belgium Bulgaria Denmark Finland France Czech Republic Estonia Hungary South America Argentina Brazil Chili North America Canada Asia China Hong Kong India South Korea Malaysia Australia Latvia Lithuania Norway Poland Romania Russia Slovakia Slovenia Ukraine A landmark trial in heart failure 6505 patients, 37 countries, 677 centres Germany Greece Ireland Italy The Netherlands Portugal Spain Sweden Turkey UK

5. www.shift-study.com   18 years  Class II to IV NYHA heart failure  Ischaemic/non-ischaemic aetiology  LV systolic dysfunction (EF  35%)  Heart rate  70 bpm  Sinus rhythm  Documented hospital admission for worsening heart failure  12 months Inclusion criteria Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81

6. www.shift-study.com Study design HR and tolerability Ivabradine 5 mg bid Matching placebo, bid Every 4 months D0 D14 D28 M4 Ivabradine 7.5/5/2.5 mg bid according to 3.5 years Screening 7 to 30 days Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81

7. www.shift-study.com Study endpoints  Cardiovascular death  Hospitalization for worsening heart failure Primary composite endpoint Other endpoints  All-cause / CV / HF death  All-cause / CV / HF hospitalization  Composite of CV death, hospitalization for HF or non-fatal MI  NYHA class / Patient & Physician Global Assessment In total population and in patients with at least 50% target dose of beta-blockers Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81

8. www.shift-study.com Patients and follow-up Median study duration: 22.9 months; maximum: 41.7 months 6558 randomized 3268 to ivabradine 3290 to placebo 3264 analysed 1 lost to follow-up 3241 analysed 2 lost to follow-up 7411 screened Excluded: 27 Excluded: 26 Swedberg K, et al. Lancet. 2010;376(9744):875-885

9. www.shift-study.com Baseline characteristics Ivabradine3241Placebo3264 Mean age, y Mean age, y60.760.1 Male, % Male, %7677 Ischaemic aetiology, % Ischaemic aetiology, %6867 NYHA II, % NYHA II, %4949 NYHA III/IV, % NYHA III/IV, %5151 Previous MI, % Previous MI, %5656 Diabetes, % Diabetes, %3031 Hypertension, % Hypertension, %6766 Swedberg K, et al. Lancet. 2010;376(9744):875-885

10. www.shift-study.com Baseline characteristics Ivabradine3241Placebo3264 Mean heart rate, bpm Mean heart rate, bpm8080 Mean LVEF, % Mean LVEF, %2929 Mean SBP, mm Hg Mean SBP, mm Hg122121 Mean DBP, mm Hg Mean DBP, mm Hg7676 eGFR, mL/min/1.73 m 2 eGFR, mL/min/1.73 m 27575 Swedberg K, et al. Lancet. 2010;376(9744):875-885

11. www.shift-study.com Chronic HF background treatment 89 91 84 61 22 3 90 91 83 59 22 4 0 10 20 30 40 50 60 70 80 90 100 Beta-blockers ACEIs and/or ARBs DiureticsAldosterone antagonists DigitalisICD/CRT Patients (%) Ivabradine Placebo Swedberg K, et al. Lancet. 2010;376(9744):875-885

12. www.shift-study.com 0 10 20 30 40 50 60 70 80 90 100 BB at randomization At least 50% target daily dose Target daily dose 89 56 26 89 56 26 Patients (%) Background beta-blocker treatment Swedberg K, et al. Lancet. 2010;376(9744):875-885 Ivabradine Placebo

13. www.shift-study.com Main reasons for not achieving beta-blocker target dose, % Ivabradinen=2099Placebon=2126 Hypotension Hypotension4445 Fatigue Fatigue3232 Dyspnea Dyspnea1414 Dizziness Dizziness1312 Bradycardia Bradycardia66 Main reasons for not prescribing beta-blocker, % Ivabradinen=344Placebon=341 COPD COPD3732 Hypotension Hypotension1720 Asthma Asthma1011 Cardiac decomp. Cardiac decomp.79 Fatigue Fatigue56 Background beta-blocker treatment Swedberg K, et al. Lancet. 2010;376(9744):875-885