1. Effects on outcomes of heart rate reduction by ivabradine in patients with congestive heart failure: is there an influence of beta-blocker dose? Systolic Heart failure treatment with the I f inhibitor ivabradine Trial www.shift-study.comSwedberg K, et al. J Am Coll Cardiol. 2012; 59:1938-1945

2. Clinical characteristics of patients by β-blocker status No BBBB <25% of target dose BB 25% to <50% of target dose BB 50% to <100% of target dose BB ≥ 100% of target dose Age, years646160 58 Resting HR, bpm84.280.679.579.178.9 Systolic BP, mm Hg121117120122125 LV EF, %28.728.128.929.429.3 NYHA III or IV, %5854495051 COPD, %3311 95 Asthma, %112222 PAD, %106665 Hypertension, %6355637073 ACE/ARB, %9086909293 Diuretic, %868783 81 Swedberg K, et al. J Am Coll Cardiol. 2012; 59:1938-1945www.shift-study.com

3. BB category (% of target dose) Placebo event rate (%) Hazard ratio 95 % CI PEP (CV death, HF hospitalisation) No β-blocker 39.30.710.55-0.93 BB, 25% 400.740.59-0.92 BB, 25% to <50% 30.80.810.68-0.98 BB, 50% to <100% 24.80.880.72-1.07 BB, ≥ 100% 20.10.990.79-1.24 HF hospitalisation No β-blocker 290.620.45-0.85 BB, 25% 290.680.52-0.89 BB, 25% to <50% 220.740.59-0.93 BB, 50% to <100% 180.830.65-1.05 BB, ≥ 100% 140.840.63-1.11 **adjusted for interaction between baseline HR and randomised treatment P heterogeneity 0.35 0.55 P Trend P Trend adj** 0.056 0.135 0.120.19 Effect of ivabradine on outcomes by β-blocker doses Swedberg K, et al. J Am Coll Cardiol. 2012; 59:1938-1945www.shift-study.com

4. <72 72 to <75 75 to <80 80 to <87 ≥87 No BBBB<25%BB ≥100% β-blocker category Baseline HR category (bpm) HR reduction according to β-blocker and HR category HR reduction (bpm) from baseline to 28 days with ivabradine* BB 25-50%BB 50-100% *Placebo corrected No impact of BB dose on HR reduction with ivabradine Impact of baseline HR on HR reduction with ivabradine Swedberg K, et al. J Am Coll Cardiol. 2012; 59:1938-1945 www.shift-study.com

5. In patients with systolic HF treated with guideline- recommended therapies, resting HR remains an important modifiable risk factor in patients treated with β-blockers When HR ≥ 70 bpm, reduction of heart rate with ivabradine will provide additional clinical benefits regardless of the ß- blocker dose The magnitude of HR reduction with ivabradine, beyond that achieved by β-blockers, primarily determines subsequent outcome Conclusion Swedberg K, et al. J Am Coll Cardiol. 2012; 59:1938-1945 www.shift-study.com