1. Heart rate in heart failure: Heart rate in heart failure: risk marker or risk factor? A subanalysis of the SHIFT trial on behalf of the Investigators M. Böhm, K. Swedberg, M. Komajda, J. Borer, I. Ford, L. Tavazzi I. Ford, L. Tavazzi

2. Disclosures SHIFT Executive Committee members received fees, research grants, or both from Servier, as well as fees for speaking or consulting from other major cardiovascular pharmaceutical companies

3.  Elevated resting heart rate is a marker of cardiovascular risk  Ivabradine slows the heart by selective I f current inhibition and has no known cardiovascular effects other than heart rate reduction  SHIFT allows to further explore the prognostic importance and pathophysiological role of heart rate in heart failure  We hypothesised that heart rate is a risk factor for cardiovascular events, and tested the effect of isolated heart rate reduction with ivabradine on outcomes in a heart failure population Heart rate and outcomes in HF: background

4. 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  Heart rate  70 bpm  Sinus rhythm  Hospital admission for worsening HF  12 months  Class II to IV NYHA heart failure  Ischaemic/non-ischaemic aetiolgoy   LV systolic dysfunction (EF  35%) Double-blind, placebo-controlled multinational study, 6505 patients median study duration: 22.9 months End of titration Mod from Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.

5. Mean heart rate reduction 70% of patients on ivabradine 7.5 mg bid 02 weeks148121620242832 Months 90 80 70 60 50 67 75 80 64 Heart rate (bpm) Placebo Ivabradine Swedberg K, et al. Lancet. 2010;online August 29.

6. HR = 0.82 P<0.0001 0612182430 Months 40 30 20 10 0 - 18% Cumulative frequency (%) HR = 0.74 P<0.0001 0612182430 20 10 0 Months - 26% Cumulative frequency (%) Primary composite endpoint Hospitalization for heart failure HR = 0.91 P=0.128 0612182430 Months 30 20 10 0 Cumulative frequency (%) Cardiovascular death Ivabradine effect on outcomes Swedberg K, et al. Lancet. 2010;online August 29. Placebo Ivabradine

7. Objective of current analysis To determine whether heart rate at baseline and on heart rate-lowering treatment with ivabradine can predict outcomes in SHIFT patients with HF and systolic dysfunction

8. Methods  The relationship between risk and heart rate was tested in the placebo group divided by quintiles of baseline heart rate  Heart rate achieved at 28 days by ivabradine (end of titration) was related to subsequent outcomes  The effect of ivabradine on outcomes, adjusted for prognostic factors at baseline, was estimated by heart rate quintiles  Outcomes analysed: –primary composite endpoint (cardiovascular death and HF hospitalisation) –secondary endpoints (all-cause / CV / death from HF; all-cause / CV / HF hospitalisation; composite of CV death, hospitalisation for HF or non-fatal MI)

9. Baseline characteristics in population divided by quintiles of heart rate Heart rate at baseline (bpm) P value* 70 - <7272 - <7575 - <8080 - <87≥87 Heart rate (bpm) 7073778296- Age (years) 636160 58<0.0001 Caucasian (%) 89928987860.0009 Smoking (%) 1514161823<0.0001 Ischaemic cause of HF (%) 7471686761<0.0001 NYHA class III/IV (%) 48 475261<0.0001 Hypertension (%) 697066 620.0007 Diabetes (%) 2630 32330.008 *p value for interaction (chi-squared test for categorical variables, Kruskal-Wallis test for continuous variables)

10. Heart rate at baseline (bpm) P value* 70 - <7272 - <7575 - <8080 - <87≥ 87 SBP (mm Hg), mean 122 1200.006 DBP (mm Hg), mean 7576 0.027 LVEF (%), mean 30 29 28<0.0001 Beta-blockers (%) 9392 8882<0.0001 ACE inhibitors (%) 81 76750.0001 Diuretics (%) 82 85860.004 Aldosterone antagonists (%) 5659 61650.0001 Cardiac glycosides (%) 18 212328<0.0001 Baseline characteristics in population divided by quintiles of heart rate *p value for interaction (chi-squared test for categorical variables, Kruskal-Wallis test for continuous variables)

11. Baseline heart rate is a predictor of endpoints on placebo Primary composite endpoint: risk increases by 3% per 1bpm increase, and by 16% per 5bpm increase 50 40 30 20 10 0 0612182430 Months ≥87 bpm 80 to <87 bpm 75 to <80 bpm 72 to <75 bpm 70 to <72 bpm P<0.001 Patients with primary composite endpoint (%) 50 40 30 20 10 0 0612182430 Months ≥87 bpm 80 to <87 bpm 75 to <80 bpm 72 to <75 bpm 70 to <72 bpm P<0.001 Patients with first hospital admission for HF (%) ≥87 bpm 80 to <87 bpm 75 to <80 bpm 72 to <75 bpm 70 to <72 bpm 50 40 30 20 10 0 0612182430 Months Patients with cardiovascular death (%) P<0.001

12. Relative risk of primary composite endpoint in the placebo group divided by quintiles of heart rate 1.02.03.00.51.52.53.5 70 - <721.00 72 - <751.15 75 - <801.33 80 - <871.80 ≥ 872.34 Heart rate at baseline (bpm) HR 1.02.03.00.51.52.53.5 70 - <721.00 72 - <751.55 75 - <801.85 80 - <872.20 ≥ 872.99 Heart rate at baseline (bpm) HR 4.04.5 1.02.03.00.51.52.5 1.00 0.87 1.03 1.64 1.85 HR 1.0 1.00 1.29 2.29 3.40 3.56 HR 2.03.04.05.06.07.08.0 Primary composite endpoint HF hospitalisation CV death Death from HF

13. Distribution of patients by classes of heart rate achieved at D28* Placebo Ivabradine Heart rate achieved at day 28 (bpm) 50 40 30 20 10 0 70 to <7565 to <7060 to <65<60 ≥75 50 40 30 20 10 0 70 to <7565 to <7060 to <65<60≥75 Patients in heart rate group (%) Heart rate achieved at day 28 (bpm) *Data exclude patients reaching primary composite endpoint in the first 28 days

14. Primary composite endpoint according to heart rate achieved at D28* in the ivabradine group *Data exclude patients reaching primary composite endpoint in the first 28 days ≥75 bpm 70-<75 bpm 60-<65 bpm 65-<70 bpm <60 bpm Patients with primary composite endpoint (%) Months 0612182430Day 28 50 40 30 20 10 0

15. Effect of ivabradine vs placebo according to heart rate at baseline (whole population) At 28 days (ivabradine group) Heart rate (bpm)59.360.362.466.172.9 Change in heart rate (bpm)- 11.1- 12.6- 14.2- 16.2- 22.5 At 28 days (placebo group) Heart rate (bpm)67.870.272.977.686.8 Change in heart rate (bpm)- 2.7 - 3.7- 4.9- 8.8 HR and 95% CI for primary composite endpoint 1.8 1.6 1.4 1.2 1.0 0.8 0.6 ≥8780 to <8775 to <8072 to <7570 to <72 Heart rate at baseline (bpm)

16. Effect of ivabradine vs placebo according to heart rate at baseline (whole population) HR and 95% CI for cardiovascular death ≥8780 to<8775 to <8072 to <7570 to <72 1.8 1.6 1.4 1.2 1.0 0.8 0.6 HR and 95% CI for first hospital admission for heart failure 8780 to <8775 to <8072 to <7570 to <72 1.8 1.6 1.4 1.2 1.0 0.8 0.6 Heart rate at baseline (bpm)

17.  Our results indicate that in heart failure patients in sinus rhythm and heart rate ≥70 bpm, there is a positive continuous relationship between baseline heart rate and increased risk  The risk is modified and significantly decreased by ivabradine, and the effect is related to heart rate at baseline and heart rate achieved at 28 days  Patients with lowest heart rates on treatment with ivabradine have the best outcomes Conclusion

18.  Elevated heart rate is a risk factor in HF  Heart rate is an important target for therapy in HF  Shifting patients to lower heart rate profiles with ivabradine reduces CV events  Lower heart rates at baseline and lower heart rates achieved on treatment are associated with better outcomes, with incremental benefit by achieving heart rate ≤60 bpm when tolerated Clinical implications

19. Available now online from Lancet http://www.lancet.comhttp://www.lancet.com published online August 29, 2010 DOI:10.1016/S0140-6736(10)61259-7