1. Effect of ivabradine on recurrent hospitalization for worsening heart failure: findings from SHIFT S ystolic H eart failure treatment with the I f inhibitor ivabradine T rial Borer JS, Böhm M, Ford I, et al. Eur Heart J. 2012;33(22):2813-2820www.shift-study.com

2.  Randomized, double-blind, placebo-controlled trial in 6505 patients to test the hypothesis that heart rate slowing with the I f inhibitor ivabradine improves cardiovascular outcomes in patients with: Moderate to severe chronic heart failure (HF) Hospitalization for worsening HF within the 12 months prior to randomization Left ventricular ejection fraction  35% Sinus rhythm and heart rate  70 bpm Receiving guidelines-based background HF therapy Trial design Swedberg K, et al. Lancet. 2010;376:875-885www.shift-study.com

3. 0612182430 Months 40 30 20 10 0 Primary endpoint: composite of CV death or hospitalization for heart failure - 18% Cumulative frequency (%) Placebo Ivabradine HR (95% CI), 0.82 (0.75–0.90) P <0.0001 Swedberg K, et al. Lancet. 2010;376:875-885www.shift-study.com

4. 0612182430 Months 30 20 10 0 Secondary pre-specified endpoint: hospitalization for heart failure - 26% Hospitalization for HF (%) Placebo Ivabradine HR (95% CI), 0.74 (0.66;0.83) P <0.0001 Swedberg K, et al. Lancet. 2010;376:875-885www.shift-study.com

5. Objective of the current analysis To assess the effect of heart rate slowing with ivabradine on recurrent hospitalizations for worsening heart failure Borer JS, Böhm M, Ford I, et al. Eur Heart J. 2012;33(22):2813-2820 www.shift-study.com

6.  Predominant reason for hospital admissions in patients with HF = worsening HF  High readmission rate after initial hospitalization: 20% within one month 50% within six months 17% are readmitted two or more times  Hospitalization = the major contributor to the cost of HF care Centers for Medicare and Medicaid Services. 2000 MedPAR data. DRG 127; Fonarow, GC. Rev Cardiovasc Med. 2002;3 (suppl 4):S3; Krumholz HM et al. R Arch Intern Med. 1997 Jan 13;157(1):99-104; Roger VL, Circulation. 2012;125(1):e2-e220. Rationale: HF hospitalization burden www.shift-study.com

7. Economic burden of chronic HF Hospitalization accounts for most CHF-associated costs Stewart S, et al. Eur J Heart Fail. 2002;4:361-71 Primary Care Outpatient referral Drug treatment Post-discharge outpatient visits Hospital admissions www.shift-study.com

8. Analysis plan  Effect of ivabradine on total hospitalizations:total hospitalizations: incidence rate ratio vs placebo repeated hospitalizations: -total-time approach (time from randomization to 1 st, 2 nd and 3 rd hospitalization) hospitalization) -gap-time approach (time from 1 st to 2 nd hospitalization)  All approaches adjusted for protocol-specified prognostic factors present pre-randomization (beta-blocker intake, NYHA class, ischaemic cause of HF, LVEF, age, SBP, HR, creatinine clearance) Borer JS, Böhm M, Ford I, et al. Eur Heart J. 2012;33(22):2813-2820 www.shift-study.com

9. Pre-randomization characteristics Number of hospitalizations for HF during trial None (n=5319) One (n=714) Two (n=254) Three or > (n=218) P-value Age (years) 60.062.361.862.4 <0.0001 Male (%) 77747781 0.18 Heart rate (bpm) 79.382.283.482.2 <0.0001 SBP (mmHg) 122.3119.8118.1117.6 <0.0001 DBP (mmHg) 76.075.073.473.3 <0.0001 LVEF (%) 29.327.627.827.1 <0.0001 NYHA class II (%) 5138 34 <0.0001 NYHA class III/IV (%) 4962 66 Duration of HF (years) 3.34.24.34.6 <0.0001 Diabetes (%) 2935 40 <0.0001 Borer JS, Böhm M, Ford I, et al. Eur Heart J. 2012;33(22):2813-2820 www.shift-study.com

10. Pre-randomization background treatment Number of hospitalizations for HF during trial None (n=5319) One (n=714) Two (n=254) Three or > (n=218) P-value Beta-blockers (%) 90898086 <0.0001 ACEI and/or ARB (%) 91899093 0.13 MRA (%) 58696773 <0.0001 Diuretics (%) 8290 95 <0.0001 Digitalis (%) 20303335 <0.0001 Borer JS, Böhm M, Ford I, et al. Eur Heart J. 2012;33(22):2813-2820 www.shift-study.com

11. 0612182430 Placebo Ivabradine 40 10 0 IRR (95% CI), 0.75 (0.65;0.87) P=0.0002 Cumulative incidence of HF hospitalizations (first and repeated) Time (months) 20 30 - 25% Effect of ivabradine on total HF hospitalizations Borer JS, Böhm M, Ford I, et al. Eur Heart J. 2012;33(22):2813-2820 www.shift-study.com

12. Effect of ivabradine on recurrence of hospitalizations for HF Total-time approach 1.20.80.6 1.0 0.4 Favours ivabradine Favours placebo First hospitalization Second hospitalization Third hospitalization Placebo (n=3264) Ivabradine (n=3241) Hazard ratio P-value P <0.001 P<0.012 514 (16%) 189 (6%) 90 (3%) 672 (21%) 283 (9%) 128 (4%) 0.75 0.66 0.71 Borer JS, Böhm M, Ford I, et al. Eur Heart J. 2012;33(22):2813-2820 www.shift-study.com

13. Recurrences of HF hospitalizations Gap-time approach = effect on 2nd hospitalisation Time from 1st hospitalization to 2nd hospitalisation frequency (%) Cumulative frequency (%) Placebo Ivabradine HR (95% CI), 0.84 (0.69-1.01) P=0.058 12 6 24 0 0 10 20 30 40 50 60 70 Time from first hospitalization (months) 472 patients with at least a first and second hospitalisation for worsening HF Borer JS, Böhm M, Ford I, et al. Eur Heart J. 2012;33(22):2813-2820 www.shift-study.com

14. Total number of hospitalizations Ivabradine (N=3241) Placebo (N=3264) IRR 95% CI p-value Hospitalization for worsening HF 90212110.750.65-0.870.0002 Hospitalization for any cause 266131100.850.78-0.940.001 Cardiovascular hospitalisation 190922720.840.76-0.940.002 Hospitalization for other than worsening of HF 175918990.920.83-1.020.12 Borer JS, Böhm M, Ford I, et al. Eur Heart J. 2012;33(22):2813-2820 www.shift-study.com

15. Limitations  Both of the statistical models have well known limitations total-time approach: treatment effect dependent on previous hospitalizations (cumulative effect) gap-time approach: restricted set of patients; therefore, randomization not preserved  Data on hospitalization burden may be influenced by differences between health care systems in different countries Borer JS, Böhm M, Ford I, et al. Eur Heart J. 2012;33(22):2813-2820 www.shift-study.com

16.  Heart rate reduction with ivabradine in patients with chronic HF, in sinus rhythm, with heart rate ≥70 bpm and already receiving guidelines-suggested therapies substantially decreases the risk of clinical deterioration as reflected by: reduction in the total hospitalizations for worsening HF reduction in the incidence of recurrent HF hospitalizations increase in time to first and subsequent hospitalizations  This benefit reduces the total burden of HF for the patient and can be expected to substantially reduce health care costs Conclusion Borer JS, Böhm M, Ford I, et al. Eur Heart J. 2012;33(22):2813-2820 www.shift-study.com