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 K, et al. J Am Coll Cardiol. 2012; 59:

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, years Resting HR, bpm Systolic BP, mm Hg LV EF, % NYHA III or IV, % COPD, % Asthma, % PAD, % Hypertension, % ACE/ARB, % Diuretic, % Swedberg K, et al. J Am Coll Cardiol. 2012; 59: www.shift-study.com

BB category (% of target dose) Placebo event rate (%) Hazard ratio 95 % CI PEP (CV death, HF hospitalisation) No β-blocker BB, 25% BB, 25% to <50% BB, 50% to <100% BB, ≥ 100% HF hospitalisation No β-blocker BB, 25% BB, 25% to <50% BB, 50% to <100% BB, ≥ 100% **adjusted for interaction between baseline HR and randomised treatment P heterogeneity P Trend P Trend adj** Effect of ivabradine on outcomes by β-blocker doses Swedberg K, et al. J Am Coll Cardiol. 2012; 59: www.shift-study.com

<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 % *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:

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: