1. A step further in the management of stable coronary patients with ivabradine

2. Rationale

3. RATIONALE  In CAD patients, high heart rate is associated with higher mortality 1  CAD patients with associated LVD are at higher risk of mortality 2  Heart rate reduction could reduce mortality in CAD patients 3  Ivabradine is a pure heart rate reducing agent with proven antianginal and anti-ischemic efficacy 4,5,6 1-.. 2- 1- Diaz A,et al. Eur Heart J. 2005;26:867-874. 2- Emond M. Circulation. 1994;90:2645–2657. 3- Cucherat Ml. Eur Heart J. 2007;28:3012-3019. 4- Borer JS et al. Circulation. 2003;107:817-823. 5- Tardif JC,et al. Eur Heart J. 2009;30:540-548 6- Tardif JC et al. Eur Heart J. 2005;26:2529-2536.

4. Design and Organization

5. Mor B idity-mortality E v A l U ation of T he I f inhibitor Ivabradine in patients with coronary disease and left ventric UL ar dysfunction  Clinical objective To examine the effects of elevated HR (>70 bpm) on cardiovascular events in these coronary patients  Pathophysiological objective To examine the effects of ivabradine on cardiovascular events in coronary patients with left ventricular dysfunction

6. Worldwide study 10 917 participants with documented coronary artery disease and left ventricular dysfunction 781 sites in 33 countries across 4 continents

7. Inclusion criteria  Male or female  Nondiabetic  55 years, diabetic  18 years  Documented coronary artery disease  Sinus rhythm and resting heart rate  60 bpm  Documented left ventricular systolic dysfunction (<40%)  Clinically stable for 3 months with regards to angina or heart failure symptoms or both  Therapeutically stable for 1 month (appropriate or stable doses of conventional medications) K. Fox et al. Am Heart J. 2006;152:860-866.

8. Design of the study Visits Follow-up for 12 to 35 months–median 19 months Ivabradine 5 mg  7.5 mg bid Placebo bid  Multicenter (781 centers / 33 countries) randomized trial  10 917 patients with stable CAD and left ventricular dysfunction (EF <40%)  Already receiving appropriate conventional cardiovascular medical therapy Fox K et al. Lancet. 2008;372:807-816.

9. Patients and follow-up Median study duration: 19 months Maximum: 35 months 10 917 randomized 5479 to ivabradine5438 to placebo 5438 analyzed5479 analyzed 12 138 screened Fox K et al. Lancet. 2008;372:807-816.

10. Baseline characteristics Values in parentheses are standard deviations PlaceboIvabradine History of diabetes (%) 373737 Time since last MI (years) 6.2 (6.0) 5.9 (5.7) 6.0 (5.9) Time since CAD diagnosis (years) 8.2 (7.1) 8.1 (7.0) 8.2 (7.0) History of hypertension (%) 717171 Previous coronary revascularization (%) 525152 All Previous MI (%) 898888 Fox K et al. Lancet. 2008;372:807-816.

11. Concomitant treatment  -blockers (%) Statins (%) Antithrombotic agents (%) Renin-angiotensin blockers (%) 87 74 94 90 Placebo 87 74 94 90 Ivabradine 87 74 94 90 All Fox K et al. Lancet. 2008;372:807-816.

12. ResultsResults

13. Years P=0.0066 Hazard ratio = 1.46 (1.11 – 1.91) 00.511.52 0 Heart rate <70 bpm Heart rate ≥70 bpm 8 % with hospitalization for fatal and nonfatal MI 0 4 6 2 Heart rate above 70 bpm increases risk of myocardial infarction by 46% risk of myocardial infarction by 46% Prospective data from the BEAUTIFUL placebo arm Fox K et al. Lancet. 2008;372:817-821.

14. % with coronary revascularization Years P=0.037 Hazard ratio = 1.38 (1.02 – 1.86) 00.511.52 0 4 6 2 Heart rate <70 bpm Heart rate ≥70 bpm Heart rate above 70 bpm increases risk of coronary revascularization by 38% risk of coronary revascularization by 38% Fox K et al. Lancet. 2008;372:817-821

15. Effect of ivabradine on primary endpoint (Overall population) % with primary composite end point of CV death, hospitalization for acute MI, or for new-onset or worsening heart failure Ivabradine Placebo P=0.94 Hazard ratio = 1.00 (0.91 – 1.10) 0 5 10 15 20 25 Years 00.511.52 Fox K et al. Lancet. 2008;372:807-816.

16. Ivabradine reduces fatal and nonfatal myocardial infarction (HR ≥70 bpm) Hospitalization for fatal or nonfatal MI (%) Placebo (HR >70 bpm) Ivabradine P=0.001 Hazard ratio = 0.64 (0.49 – 0.84) Years 00.511.52 0 4 8 RRR 36% RRR: relative risk reduction Fox K et al. Lancet. 2008;372:807-816.

17. HR >70 bpm in placebo (mean HR = 79 bpm) *P=0.001 **P=0.0066 Years Hospitalization for fatal or nonfatal MI (%) HR > 70 bpm with Procoralan (mean HR = 66 bpm after treatment) 00.511.52 0 4 8 HR <70 bpm in placebo (mean HR = 64 bpm) Ivabradine shifts the patients from high risk to low risk -36%*

18. Years 00.511.52 0 4 Ivabradine 8 Coronary revascularization (%) P=0.016 Hazard ratio = 0.70 (0.52 – 0.93) RRR 30% Placebo (HR >70 bpm) Ivabradine reduces the need for revascularization (HR ≥70 bpm) RRR: relative risk reduction Fox K et al. Lancet. 2008;372:807-816.

19. 0.11431%0.69 Fatal MI 0.02322%0.78 Fatal and nonfatal MI or unstable angina 0.01630%0.70 Coronary revascularization 0.00923%0.77 Fatal and nonfatal MI, unstable angina, or revascularization 0.00136%0.64 Fatal and nonfatal MI P value Risk reduction Hazard ratio Predefined end point Ivabradine reduces all coronary events in coronary patients with HR ≥70 bpm Fox K et al. Lancet. 2008;372:807-816.

20. Optimal reduction in heart rate in coronary patients with HR ≥70 bpm Heart rate (bpm) Follow-up (days) 50 60 80 0 153090 180 360 540 720 70 Placebo Ivabradine 90 Fox K, et al. Lancet. 2008;372:807-816.

21. New Results In angina patients

22.  Rationale Angina is the most common clinical manifestation of coronary artery disease (CAD). Procoralan has established anti-ischemic and antianginal efficacy. In the large BEAUTIFUL trial, Procoralan demonstrates that it reduces coronary events in CAD patients.  Objective To explore the effects of Procoralan on cardiovascular outcomes in BEAUTIFUL patients with limiting angina at baseline. New results in angina patients

23. Design and methodology 1507 randomized with angina 734 to Procoralan 773 to placebo 773 analyzed 734 analyzed 12 138 patients with CAD and LVD screened 10 917 randomized Fox K, Ford I, et al; BEAUTIFUL Investigators. Effect of ivabradine on cardiovascular outcomes in patients with stable coronary artery diseaseand left-ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Data on file. New results in angina patients

24. Baseline treatment Patients with anginaTotal BEAUTIFUL population Ivabradine (n=734) Placebo (n=773) IvabradinePlacebo Aspirin or antithrombotic agent 92% 94% Statin 67%64%74% ACE inhibitor and/or ARB 88%86%90% β-Blocker 89%90%87% Fox K, Ford I, et al; BEAUTIFUL Investigators. Effect of ivabradine on cardiovascular outcomes in patients with stable coronary artery diseaseand left-ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur heart Jour On line. New results in angina patients

25. Ivabradine reduces primary end point in angina patients Primary end point(PEP) : CV death + hospitalization for HF or MI Fox K, Ford I, et al; BEAUTIFUL Investigators. Effect of ivabradine on cardiovascular outcomes in patients with stable coronary artery diseaseand left-ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur heart Jour On line. New results in angina patients

26. Ivabradine reduces myocardial infarction in patients with angina All patients with angina Patients with angina and heart rate >70 bpm Placebo Ivabradine Hospitalization for fatal and nonfatal MI HR (95% CI), 0.58 (0.37–0.92); P=0.021 Years 0 5 10 15 00.511.52 Event rate (%) 42% Placebo Ivabradine Hospitalization for fatal and nonfatal MI HR (95% CI), 0.27 (0.11–0.66); P=0.002 Years 0 5 10 15 00.511.52 Event rate (%) 73% Fox K, Ford I, et al; BEAUTIFUL Investigators. Effect of ivabradine on cardiovascular outcomes in patients with stable coronary artery diseaseand left-ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur heart Jour On line. New results in angina patients

27. Summary of observed cardiovascular risk reduction in angina patients 24% 0.76 Primary composite end point 12%0.88CV death 42%0.58 16%0.84Hospitalization for HF 13%0.87All-cause mortality Risk reduction Hazard ratio Predefined end point 30%0.70Coronary revascularization Hospitalization for MI (n=1507) Fox K, Ford I, et al; BEAUTIFUL Investigators. Effect of ivabradine on cardiovascular outcomes in patients with stable coronary artery diseaseand left-ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur heart Jour On line. New results in angina patients

28.  Ivabradine, the first selective and specific I f inhibitor, has already demonstrated antianginal and anti-ischemic efficacy and improvement of cardiac performance  BEAUTIFUL, the first morbidity-mortality trial with ivabradine, includes 10 917 patients with documented stable coronary artery disease and left ventricular dysfunction receiving optimal guidelines-based therapy. –In patients with coronary artery disease and left ventricular dysfunction, those with a heart rate >70 bpm have a higher risk of cardiovascular mortality, hospitalization for myocardial infarction, and heart failure. –In patients with heart rate >70 bpm, ivabradine reduces the composite of fatal and nonfatal myocardial infarction and reduces the need for revascularisation. –In angina patients, ivabradine reduces the primary end point of cardiovascular death, hospitalization for heart failure, or for myocardial infarction. In brief

29. Organization Executive Committee: K. Fox (Chairman), R. Ferrari, M. Tendera, P.G. Steg, I. Ford Steering Committee: R. Ferrari (Chairman), Y. Belenkov (Russia), J. Borbola (Hungary), R. Capalneanu (Romania), B. Eber (Austria), J. Eha (Estonia), N. Danchin (France), M. Dellborg (Sweden), K. Dickstein (Norway), B. Finkov and Y. Yotov (Bulgaria), B. Freedman (Australia), H. Grancelli (Argentina), A. Hall (United Kingdom), P. Hildebrandt (Denmark), J. Hradec (Czech Republic), D. Hu and C. Lau (China/Hong Kong), J. Jirgensons (Latvia), A. Laucevicius (Lithuania), T.U. Lqscher (Switzerland), C. Macaya (Spain), A. Maggioni (Italy), T. Meinertz (Germany), D. Mulcahy (Ireland), J. Murin (Slovakia), A. Oto (Turkey), A. Parkhomenko (Ukraine), K. Peuhkurinen (Finland), P. Rakovec (Slovenia), W. Ruzyllo (Poland), R. Seabra-Gomes (Portugal), J.C. Tardif (Canada), W. Van Gilst (The Netherlands), J.L. Vanoverschelde (Belgium), P. Vardas (Greece) End Point Validation Committee: K. Thygesen (Chairman); M. Frenneaux; G. Jondeau Data Monitoring Committee: A.J. Camm (Chairman); G. Murray; H. Dargie, L. Tavazzi