1. S ystolic H eart failure treatment with the I f inhibitor ivabradine T rial Main results www.shift-study.com Swedberg K, et al. Lancet. 2010;376(9744):875-885

2. 0612182430 40 30 20 10 0 Primary composite endpoint (CV death or hospital admission for worsening HF) 18% Cumulative frequency (%) Placebo Ivabradine HR = 0.82 (0.75–0.90) P < 0.0001 Months www.shift-study.com Swedberg K, et al. Lancet. 2010;376(9744):875-885

3. 0612182430 20 10 0 Hospitalization Hospitalization for HF 26% Placebo Ivabradine HR = 0.74 (0.66–0.83) P < 0.0001 Months Cumulative frequency (%) www.shift-study.com Swedberg K, et al. Lancet. 2010;376(9744):875-885

4. Death from heart failure 26% 0612182430 10 5 0 HR = 0.74 (0.58–0.94) P = 0.014 Placebo Ivabradine Months Cumulative frequency (%) www.shift-study.com Swedberg K, et al. Lancet. 2010;376(9744):875-885

5. Effect of ivabradine on outcomes Endpoints Hazard ratio 95% CI p value Primary composite endpoint (CV death or hospital admission for worsening HF)0.82[0.75;0.90] p<0.0001 All-cause mortality0.90[0.80;1.02] p=0.092 Death from heart failure0.74[0.58;0.94] p=0.014 All-cause hospital admission0.89[0.82;0.96] p=0.003 Any CV hospital admission0.85[0.78;0.92] p=0.0002 CV death/hospital admission for HF or non-fatal MI0.82[0.74;0.89] p<0.0001 www.shift-study.com Swedberg K, et al. Lancet. 2010;376(9744):875-885

6. Age <65 years ≥65 years Sex Male Female Beta-blockers No Yes Aetiology of heart failure Non-ischaemic Ischaemic NYHA class NYHA class II NYHA class III or IV Diabetes No Yes Hypertension No Yes Baseline heart rate <77 bpm ≥77 bpm Test for interaction P = 0.029 1.51.00.5 Hazard ratio Favours ivabradineFavours placebo Effect of ivabradine in prespecified subgroups www.shift-study.com Swedberg K, et al. Lancet. 2010;376(9744):875-885

7. 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 www.shift-study.com Swedberg K, et al. Lancet. 2010;376(9744):875-885

8. NYHA class changes 28 68 5 24 70 6 0 10 20 30 40 50 60 70 ImprovementStabilityWorsening P = 0.0003 Patients (%) Ivabradine Placebo www.shift-study.com Swedberg K, et al. Lancet. 2010;376(9744):875-885

9. Incidence of selected adverse events (n = 6492) Patients with an event Ivabradine N=3232, n (%) Placebo N=3260, n (%) p value All serious adverse events 1450 (45%) 1553 (48%) 0.025 All adverse events 2439 (75%) 2423 (74%) 0.303 Symptomatic bradycardia 150 (5%) 32 (1%) <0.0001 Asymptomatic bradycardia 184 (6%) 48 (1%) <0.0001 Atrial fibrillation 306 (9%) 251 (8%) 0.012 Phosphenes89 (3%) 17 (1%) <0.0001 Blurred vision 17 (1%) 7 (<1%) 0.042 www.shift-study.com Swedberg K, et al. Lancet. 2010;376(9744):875-885

10. Patients with an adverse event, leading to withdrawal Ivabradine N=3232, n (%) Placebo N=3260, n (%) p value All adverse events467 (14%) 416 (13%) 0.051 Symptomatic bradycardia20 (1%) 5 (<1%) 0.002 Asymptomatic bradycardia28 (1%) 5 (<1%) <0.0001 Atrial fibrillation135 (4%) 113 (3%) 0.137 Phosphenes7 (<1%) 3 (<1%) 0.224 Blurred vision1 (<1%) 1.000 Treatment discontinuation www.shift-study.com Swedberg K, et al. Lancet. 2010;376(9744):875-885

11. Ivabradine significantly reduces major risks associated with heart failure:  18% reduction in CV death or hospital admission for worsening HF  26% reduction in death from heart failure  26% reduction in hospital admission for worsening heart failure Benefits are apparent early, are consistent in predefined subgroups, and have been demonstrated on top of recommended therapy Treatment is well tolerated Conclusion www.shift-study.com Swedberg K, et al. Lancet. 2010;376(9744):875-885