1. Influence of background treatment with mineralocorticoid receptor antagonists on ivabradine's effects in patients with chronic heart failure Systolic Heart failure treatment with the I f inhibitor ivabradine Trial Komajda M, Böhm M, Borer J et al. Eur J Heart Fail. 2013;15(1):79-84www.shift-study.com

2. Objective To explore whether ivabradine is beneficial in patients with systolic HF, in sinus rhythm, with resting HR ≥70 bpm, and whose guideline-recommended background therapy includes mineralocorticoid receptor antagonist Komajda M, Böhm M, Borer J, et al. Eur J Heart Fail. 2013;15(1):79-84www.shift-study.com

3. Statistical method Effect of ivabradine was assessed separately in patients with and without MRA at baseline using a time-to-first-event survival analysis (a Cox’s proportional hazards model including treatment effect and adjusted for prognostic factors at baseline such as BB intake, HR, NYHA class, LVEF, ischaemic cause of HF, age, SBP, EGFR) p value for interaction between treatment and presence or not of MRA was provided by adding this interaction to the Cox model Komajda M, Böhm M, Borer J, et al. Eur J Heart Fail. 2013;15(1):79-84www.shift-study.com

4. Baseline characteristics With MRA n=3922 Without MRA n=2583P Mean age, years Mean age, years5962 <0.0001 Male, % Male, %7678 0.0782 Mean BMI, kg/m 2 Mean BMI, kg/m 22828 0.0013 Mean HF duration, years Mean HF duration, years34 0.0551 HF ischemic cause, % HF ischemic cause, %6376 <0.0001 NYHA class II, % NYHA class II, %4554 <0.0001 NYHA class III, % NYHA class III, %5345 Mean LVEF, % Mean LVEF, %2830 <0.0001 Mean HR, bpm Mean HR, bpm8079 <0.0001 Mean systolic BP, mm Hg Mean systolic BP, mm Hg119126 <0.0001 Mean diastolic BP, mm Hg Mean diastolic BP, mm Hg7577 <0.0001 Komajda M, Böhm M, Borer J, et al. Eur J Heart Fail. 2013;15(1):79-84www.shift-study.com

5. Baseline background treatment With MRA n=3922 Without MRA n=2583P β-Blocker, % β-Blocker, %9089 0.2477 ACE inhibitor/ARB, % ACE inhibitor/ARB, %9191 0.7292 Diuretic (excludes AA), % Diuretic (excludes AA), %8876 <0.0001 Digitalis, % Digitalis, %2813 <0.0001 Komajda M, Böhm M, Borer J, et al. Eur J Heart Fail. 2013;15(1):79-84www.shift-study.com

6. Effect of ivabradine on heart rate Mean HR, bpmMean change in HR, bpm BaselineM1-baselineM12-baseline Patients with MRA n=1981 80.0  9.5 -15.4  10.7 -14.3  12.4 Patients without MRA n=1260 79.3  9.4 -15.3  10.8 -14.3  11.7 Komajda M, Böhm M, Borer J, et al. Eur J Heart Fail. 2013;15(1):79-84www.shift-study.com

7. Effect of ivabradine on major outcomes 1.6 0.4 0.8 0.61.0 1.4 1.2 Favors ivabradine Favors placebo Ivabradine Placebo Hazard ratio* p interaction Primary endpoint With MRA, n=3922 28% 33% 0.82 Without MRA, n=2583 19% 23% 0.81 Cardiovascular death 16% 18% 0.88 11% 1.02 Hospitalization for HF 19% 23% 0.77 11% 17% 0.67 Death from any cause 17% 19% 0.88 13% 0.99 Death from heart failure 4% 6% 0.73 3% 0.80 0.916 0.279 0.304 0.366 0.723 With MRA, n=3922 Without MRA, n=2583 With MRA, n=3922 Without MRA, n=2583 With MRA, n=3922 Without MRA, n=2583 With MRA, n=3922 Without MRA, n=2583 * adjusted for prognostic factors at baseline Komajda M, Böhm M, Borer J, et al. Eur J Heart Fail. 2013;15(1):79-84www.shift-study.com

8. SafetyIvabradinen=1977Placebon=1938Ivabradinen=1255Placebon=1322 Serious adverse events, %44*484042 Adverse events leading to withdrawal, % 15141311 Emergent adverse events, %75 72 Selected adverse events, % Sym/ bradycardia Asym/ bradycardia Atrial fibrillation Hyperkalemia Renal failure Phosphenes 4* 5* 9 1 2 3* <1 1 7 2 <1 5* 6* 8 <1* 1* 3* 1 6 2 3 <1 * Differences is significant Komajda M, Böhm M, Borer J, et al. Eur J Heart Fail. 2013;15(1):79-84www.shift-study.com

9.  Ivabradine improves outcomes in the SHIFT population receiving or not aldosterone antagonists and the magnitude of the improvement is similar in the two groups  The addition of ivabradine should be considered in patients with heart failure with reduced LVEF, sinus rhythm and heart rate of 70 bpm or higher, whatever their background neurohormonal treatment Conclusion Komajda M, Böhm M, Borer J, et al. Eur J Heart Fail. 2013;15(1):79-84www.shift-study.com