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

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

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

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  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 mortality1 • CAD patients with associated LVD are at higher risk of mortality2 • Heart rate reduction could reduce mortality in CAD patients3 • Ivabradine is a pure heart rate reducing agent with proven antianginal and anti-ischemic efficacy 4,5,6 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. MorBidity-mortality EvAlUation of The If inhibitor Ivabradine in patients with coronary disease and left ventricULar dysfunction • Clinical objective To examine the effects of ivabradine on cardiovascular events in coronary patients with left ventricular dysfunction • Pathophysiological objective To examine the effects of elevated HR (>70 bpm) on cardiovascular events in these coronary patients

  6. Worldwide study 10 917 participants with documented coronary artery diseaseand 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 orheart failure symptoms or both • Therapeutically stable for 1 month (appropriate or stable dosesof conventional medications) K. Fox et al. Am Heart J. 2006;152:860-866.

  8. Design of the study Ivabradine 5 mg  7.5 mg 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 Placebo bid Visits Follow-up for 12 to 35 months–median 19 months Fox K et al. Lancet. 2008;372:807-816.

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

  10. Baseline characteristics Placebo Ivabradine All Time since CAD diagnosis(years) 8.2 (7.1) 8.1 (7.0) 8.2 (7.0) Previous MI (%) 89 88 88 Time since last MI (years) 6.2 (6.0) 5.9 (5.7) 6.0 (5.9) History of diabetes (%) 37 37 37 History of hypertension (%) 71 71 71 Previous coronaryrevascularization (%) 52 51 52 Values in parentheses are standard deviations Fox K et al. Lancet. 2008;372:807-816.

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

  12. Results

  13. 0 0.5 1 1.5 2 Heart rate above 70 bpm increases risk of myocardial infarction by 46% Prospective data from the BEAUTIFUL placebo arm 8 Hazard ratio = 1.46 (1.11 – 1.91) P=0.0066 Heart rate ≥70 bpm 6 % with hospitalization for fatal and nonfatal MI 4 Heart rate <70 bpm 2 0 0 Years Fox K et al. Lancet. 2008;372:817-821.

  14. Hazard ratio = 1.38 (1.02 – 1.86) P=0.037 0 0.5 1 1.5 2 Heart rate above 70 bpm increases risk of coronary revascularization by 38% % with coronary revascularization 6 Heart rate ≥70 bpm 4 2 Heart rate <70 bpm 0 Years Fox K et al. Lancet. 2008;372:817-821

  15. 25 Hazard ratio = 1.00 (0.91 – 1.10) P=0.94 Ivabradine 20 15 Placebo 10 5 0 0 0.5 1 1.5 2 Years Effect of ivabradine on primaryendpoint (Overall population) % with primary composite end point of CV death, hospitalization for acute MI, or for new-onset or worsening heart failure Fox K et al. Lancet. 2008;372:807-816.

  16. Hazard ratio = 0.64 (0.49 – 0.84) P=0.001 Ivabradine reduces fatal and nonfatal myocardial infarction (HR ≥70 bpm) 8 Placebo (HR >70 bpm) RRR 36% Hospitalization for fatal or nonfatal MI (%) 4 Ivabradine 0 0 0.5 1 1.5 2 Years RRR: relative risk reduction Fox K et al. Lancet. 2008;372:807-816.

  17. -36%* HR > 70 bpm with Procoralan (mean HR = 66 bpm after treatment) Ivabradine shifts the patients from high risk to low risk 8 HR >70 bpm in placebo (mean HR = 79 bpm) 4 HR <70 bpm in placebo(mean HR = 64 bpm) Hospitalization for fatal or nonfatal MI (%) 0 *P=0.001 **P=0.0066 0 0.5 1 1.5 2 Years Fox K et al. Lancet. 2008;372:807-816.

  18. 0 0.5 1 1.5 2 Ivabradine reduces the need for revascularization (HR ≥70 bpm) 8 Hazard ratio = 0.70 (0.52 – 0.93) P=0.016 Placebo (HR >70 bpm) RRR 30% Coronary revascularization (%) 4 Ivabradine 0 Years RRR: relative risk reduction Fox K et al. Lancet. 2008;372:807-816.

  19. Fatal MI 0.69 31% 0.114 Fatal and nonfatal MI 0.64 36% 0.001 Fatal and nonfatal MI or unstable angina 0.78 22% 0.023 Fatal and nonfatal MI, unstable angina,or revascularization 0.77 23% 0.009 Coronary revascularization 0.70 30% 0.016 Ivabradine reduces all coronary events in coronary patients with HR ≥70 bpm Predefined end point Hazardratio Riskreduction P value Fox K et al. Lancet. 2008;372:807-816.

  20. Optimal reduction in heart rate in coronary patients with HR ≥70 bpm 90 80 Placebo 70 Heart rate (bpm) 60 Ivabradine 50 540 0 360 720 180 15 30 90 Follow-up (days) Fox K, et al. Lancet. 2008;372:807-816.

  21. New Results In angina patients

  22. New results in angina patients • 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.

  23. Design and methodology New results in angina patients 12 138 patients with CAD and LVD screened 10 917 randomized 1507 randomized with angina 773 to placebo 734 to Procoralan 773 analyzed 734 analyzed 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.

  24. Baseline treatment New results in angina patients Patients with angina Total BEAUTIFUL population • Ivabradine (n=734) • Placebo(n=773) Ivabradine • Placebo Aspirin or antithrombotic agent • 92% • 92% • 94% • 94% • Statin • 67% • 64% • 74% • 74% ACE inhibitor and/or ARB • 88% • 86% • 90% • 90% • β-Blocker • 89% • 90% • 87% • 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.

  25. 20 Placebo -24% n=1507 P=0.05 15 Cumulative incidence for PEP* (%) Ivabradine 10 5 0 0 0.5 1 1.5 2 Years Ivabradine reduces primary end point in angina patients New results 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.

  26. 15 15 Hospitalization for fatal and nonfatal MI HR (95% CI), 0.58 (0.37–0.92); P=0.021 Hospitalization for fatal and nonfatal MI HR (95% CI), 0.27 (0.11–0.66); P=0.002 42% 73% 10 10 Placebo Event rate (%) Placebo Event rate (%) 5 5 Ivabradine Ivabradine 0 0 0 0.5 1 1.5 2 0 0.5 1 1.5 2 Years Years Ivabradine reduces myocardial infarction in patients with angina New results in angina patients Patients with angina and heart rate >70 bpm All patients with angina 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.

  27. Hazardratio Riskreduction Predefined end point 0.76 Primary composite end point 24% All-cause mortality 0.87 13% CV death 0.88 12% Hospitalization for HF 0.84 16% Hospitalization for MI 0.58 42% Coronary revascularization 0.70 30% Summary of observed cardiovascular risk reduction in angina patients New results in angina patients (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.

  28. In brief • Ivabradine, the first selective and specific If 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.

  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

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