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 Jeffrey S Borer on behalf of M Böhm, I Ford, M Komajda, L Tavazzi, J Lopez-Sendon, M Alings, E Lopez-de-Sa, K Swedberg, and SHIFT Investigators

2. Disclosures The author and all co-authors are paid consultants to Servier, manufacturer of ivabradine

3. the I f inhibitor ivabradine improves cardiovascular outcomes in patients with  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)Moderate to severe chronic heart failure (HF) Hospitalization for worsening HF within the 12 months prior to randomizationHospitalization for worsening HF within the 12 months prior to randomization Left ventricular ejection fraction  35%Left ventricular ejection fraction  35% Sinus rhythm and heart rate 70 bpmSinus rhythm and heart rate  70 bpm Receiving guidelines-based background HF therapyReceiving guidelines-based background HF therapy Trial design Swedberg K, et al. Lancet 2010;376: 875-885.

4. 0612182430 Months 40 30 20 10 0 Primary endpoint: c omposite 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: 875-885.

5. 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: 875-885.

6. Objective of the current analysis To assess the effect of heart rate slowing with ivabradine on recurrent hospitalizations for worsening heart failure

7.  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

8. Economic burden of chronic HF: Hospitalization accounts for most CHF-associated costs. Stewart S et al. Eur J Heart Fail 2002;4:361–71.

9. Analysis Plan Effect of ivabradine onEffect of ivabradine on total hospitalizations: incidence rate ratio vs placebototal hospitalizations: incidence rate ratio vs placebo repeated hospitalizations:repeated hospitalizations: (time from randomization to 1 st, 2 nd and 3 rd hospitalization)total-time approach (time from randomization to 1 st, 2 nd and 3 rd hospitalization) gap-time approach (time from 1 st to 2 nd 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, LV ejection fraction, age, systolic blood pressure, heart rate, creatinine clearance)All approaches adjusted for protocol-specified prognostic factors present pre-randomization (beta-blocker intake, NYHA class, ischaemic cause of HF, LV ejection fraction, age, systolic blood pressure, heart rate, creatinine clearance)

10. 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

11. 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

12. 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

13. 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

14. Recurrences of HF hospitalizations Gap-time approach = effect on 2nd hospitalisation Time from 1st hospitalization to 2nd hospitalisation Recurrences of HF hospitalizations Gap-time approach = effect on 2nd hospitalisation Time from 1st hospitalization to 2nd hospitalisation n=1186 with a first hospitalization 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)

15. Total number of hospitalizations Ivabradine (N=3241) Placebo (N=3264) IRR(*) 95% CI p-value Hospitalization WHF 90212110.750.65-0.870.0002 Hospitalization any cause 266131100.850.78-0.940.001 Cardiovascular hospitalisation 190922720.840.76-0.940.002 Hospitalization other than WHF 175918990.920.83-1.020.12

16. 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

17.  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

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