1. May 23rd, 2012 Hot topics from the Heart Failure Congress in Belgrade

2. Our presenters today Prof M. Komajda Co-chairman of the SHIFT Executive Committee Head of the Cardiovascular Department Pitié-Salpêtrière Hospital Paris, FRANCE Prof S. Anker Professor of cardiology: Division of Applied Cachexia Research Department of cardiology, Charité Campus Virchow-Klinikum Berlin, Germany

3. The program The new 2012 ESC Guidelines for heart failure New evidence from the SHIFT trial (Late Breaking Session) Questions and answers 10’ 15’

4. Prof S. Anker The new 2012 ESC Guidelines for management of heart failure

5. The new 2012 ESC Guidelines for acute and chronic heart failure 26 Task Force Members Avaivable online www.escardio.org

6. The principal changes from the 2008 guidelines 1.An expansion of the indication for mineralocorticoid receptor antagonists (MRAs) 2.A new indication for the sinus node inhibitor ivabradine 3.An expanded indication for cardiac resynchronization therapy (CRT) 4.New information on the role of coronary revascularization in HF 5.Recognition of the growing use of ventricular assist devices 6.The emergence of transcatheter valve interventions 7.Addition of MR-proANP to biomarkers for HF diagnosis

7. Diagnostic flowchart for patients with suspected heart failure—showing alternative ‘echocardiography first’ (blue) or ‘natriuretic peptide first’ (red) approaches.

8. Pharmacological therapy for CHF patients

9. Update on pharmacological therapy: expansion of the indication for MRA

10. Update on pharmacological therapy: a new indication for ivabradine for patients with CHF

12. Further treatment options for patients with CHF

13. Update on implanted devices: an expanded indication for CRT

14. New information on the role of coronary revascularization in systolic HF

15. 6 deaths 9 hospitalisations 15 deaths 30 hospitalisations RCT of “low” vs. “normal” sodium diet in systolic CHF Lack of robust evidence for most lifestyle, non-pharmacological interventions

16. Lifestyle and non-pharmacological interventions

17. Management programmes for patients with heart failure

18. New evidence from the trial Presentations at Late Breaking Trials and Rapid Fire sessions Prof M. Komajda

19. Primary objective of the main trial To evaluate whether the I f inhibitor ivabradine improves cardiovascular outcomes in patients with 1. Moderate to severe chronic heart failure 1. Moderate to severe chronic heart failure 2. Left ventricular ejection fraction  35% 2. Left ventricular ejection fraction  35% 3. Heart rate 70 bpm and in sinus rhythm 3. Heart rate  70 bpm and in sinus rhythm 4. Recommended therapy 4. Recommended therapy

20. Hazard ratio p value Main study results: effect of ivabradine on major outcomes Primary composite endpoint 0.82 <0.0001 All cause mortality0.90 0.092 Cardiovascular death0.91 0.128 Death from HF0.74 0.014 All-cause hospital admission 0.89 0.003 Hospitalization for HF0.74 <0.0001 Any CV hospitalization 0.85 0.0002 CV death/hospitalization for HF 0.82 <0.0001 or non-fatal MI 0.5 0.60.70.8 0.9 1.0 1.1 Swedberg K, et al. Lancet 2010;376: 875-885.

21. New findings: Ivabradine reduces mortality and other major outcomes in chronic systolic heart failure: analysis in high risk patients with HR ≥ 75 bpm Systolic Heart failure treatment with the I f inhibitor ivabradine Trial Presentation at Rapid Fire Session, Sunday 20 May 2012

22. Rationale  SHIFT and other heart failure studies showed a continuous increase in risk with increasing heart rate  64% of the patients enrolled in SHIFT had a heart rate ≥ 75 bpm  A cut-off of ≥75 bpm was chosen by the EMA for the approval of ivabradine in chronic heart failure

23. 1.00 Primary composite end point Cardiovascular mortality Hospitalization for worsening HF Death from HF All-cause mortality All-cause hospitalization Any cardiovascular hospitalization 0.76 0.68-0.85 0.83 0.71-0.97 0.70 0.61-0.80 0.61 0.46-0.81 0.83 0.72-0.96 0.82 0.75-0.90 0.79 0.71-0.88 0.20 <0.0001 0.0166 <0.0001 0.0006 0.0109 <0.0001 P P Hazard ratio 1.200.400.600.80 Effect of ivabradine on major outcomes in patients with HR  75 bpm Favors ivabradineFavors placebo 95% CI Böhm M, et al. Clin Res Cardiol. Online 11 May 2012.

24. Effect of ivabradine on outcomes according to HR achieved at 28 days 06121824 40 10 0 Time (months) 20 30 Patients with primary composite end point (%) Day 28  75 bpm 70 to <75 bpm 65 to <70 bpm 60 to <65 bpm <60 bpm Böhm M, et al. Clin Res Cardiol. Online 11 May 2012.

25. Effect of ivabradine on outcomes according to magnitude of HR reduction 06121824 40 10 0 20 30 Day 28 Time (months) Patients with primary composite end point (%)  0 bpm -10 to <0 bpm < -10 bpm Böhm M, et al. Clin Res Cardiol. Online 11 May 2012.

26. Available online now

27. New findings: Heart rate reduction, not dose of beta-blocker, key to ivabradine success in heart failure Systolic Heart failure treatment with the I f inhibitor ivabradine Trial Presentation at Late Breaking Trials, Sunday 20 May 2012

28. Five patient categories according to beta-blocker status: No BB / 100 % target dose Five patient categories, according to baseline heart rate: <72 bpm / 72 - 74 / 75 - 79 / 80 – 86 / ≥ 87 bpm Subgroups by beta-blocker dose and heart rate Swedberg K, et al. J Am Coll Cardiol 2012; 59:1938-1945

29. Clinical characteristics No BBBB <25%BB 25% to <50%BB 50% to <100% BB ≥ 100% Age, years646160 58 Resting HR, bpm848179 Systolic BP, mm Hg121117120122125 LVEF, %292829 NYHA III or IV, %5854495051 COPD, %3311 95 Asthma, %112222 PAD, %106665 Hypertension, %6355637073 ACE/ARB, %9086909293 Diuretics, %868783 81 Swedberg K, et al. J Am Coll Cardiol 2012; 59:1938-1945

30. <72 72 to <75 75 to <80 80 to <87 ≥87 No BBBB<25%BB ≥100% Beta-blocker category Baseline HR category (bpm) HR reduction according to on beta-blocker and HR category HR reduction from baseline to 28 days with ivabradine* (bpm) 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

31. BB category (% of target dose) Placebo event rate (%) Hazard ratio 95 % CI PEP (CV death, HF hospitalisation) No BB 39.30.71 0.55-0.93 BB (<25) 400.74 0.59-0.92 BB (25 - 49) 30.80.81 0.68-0.98 BB (50 – 99) 24.80.88 0.72-1.07 BB ( ≥ 100) 20.10.99 0.79-1.24 HF hospitalisation No BB 290.62 0.45-0.85 BB (<25) 290.68 0.52-0.89 BB (25 – 49) 220.74 0.59-0.93 BB (50 - 99) 180.83 0.65-1.05 BB ( ≥ 100) 140.84 0.63-1.11 P Heterogeneity 0.35 0.55 P Trend P Trend adj** 0.056 0.135 0.120.19 Effect of ivabradine on outcomes by beta-blocker doses Swedberg K, et al. J Am Coll Cardiol 2012; 59:1938-1945

32. Available online now Swedberg K, et al. J Am Coll Cardiol 2012; 59:1938-1945

33. New findings: The effect of ivabradine on outcomes in patients with or without aldosterone antagonists Systolic Heart failure treatment with the I f inhibitor ivabradine Trial

34. Chronic HF background treatment 89 91 84 61 22 3 90 91 83 59 22 4 0 10 20 30 40 50 60 70 80 90 100 Beta-blockersACEIs and/or ARBs DiureticsAldosterone antagonists DigitalisICD/CRT Ivabradine Placebo Patients (%) Swedberg K, et al. Lancet. 2010;376:875-885.

35. Type and dose of aldosterone antagonists 3922 patients had aldosterone antagonist (AA) at baseline: Spironolactone: 3783 patients (mean dose = 34.7 mg) Eplerenone: 100 patients (mean dose = 28.8 mg) Other: 39 patients Komajda et al. Late breaking trial. Heart Failure 2012

36. Baseline characteristics With AA n=3922 Without AA n=2583 P Mean age, years5962 <0.0001 Male, %7678 0.0782 Mean BMI, kg/m 2 28 0.0013 Mean HF duration, years34 0.0551 HF ischemic cause, %6376 <0.0001 NYHA class II, %4554 <0.0001 NYHA class III, %5345 Mean LVEF, %2830 <0.0001 Mean HR, bpm8079 <0.0001 Mean systolic BP, mm Hg 119126 <0.0001 Mean diastolic BP, mm Hg 7577 <0.0001 Komajda et al. Late breaking trial. Heart Failure 2012

37. Death from HF Patients (%) 33 23 Patients with AA (n=1941) Patients without AA (n=1323) Primary endpoint 0 10 30 20 40 All-cause mortality 19 13 CV death 18 11 6 50 HF Hosp. 23 17 HR=1.40* HR=1.40** P<0.0001; ** P=0.0004; *** P=0.0667 HR=1.50* HR=1.41*** HR=1.35** Event rate in placebo group Komajda et al. Late breaking trial. Heart Failure 2012 3

38. 1.6 0.4 0.8 0.61.0 1.4 1.2 Favors ivabradineFavors placebo Ivabradine Placebo Hazard ratio* P interaction Primary endpoint (%) With AA, n=3922 28 33 0.82 Without AA, 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 HF (%) 4 6 0.73 3 3 0.80 0.916 0.279 0.304 0.366 0.723 With AA Without AA With AA Without AA With AA Without AA With AA Without AA Effect of ivabradine on major outcomes Komajda et al. Late breaking trial. Heart Failure 2012

39. Conclusion The results of new analysis are consistent with the main results of SHIFT, demonstrating that HR reduction with ivabradine prevents adverse CV outcomes In patients with HR ≥75 bpm, ivabradine significantly reduces all major outcomes, including all-cause death and CV death The magnitude of the effect is similar in patients taking or not aldosterone antagonists The magnitude of HR reduction with ivabradine, not the dose of beta-blockers, determines improvement of outcome

40. Ivabradine in the management of systolic CHF: new ESC Guideline