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Ivabradine

Ivabradine. Dr.Rajesh Rajan M.D.,D.Card,FACC,FAHA,FESC PRESIDENT – IACC www.accindia.org. 1. Elevated Resting Heart Rate. Accelerates production of atherosclerosis (Int J Cardiol 2008;126:302-12) Associated with coronary plaque disruption (Circulation 2001;126:1477-82) Framingham Study

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Ivabradine

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  1. Ivabradine Dr.Rajesh RajanM.D.,D.Card,FACC,FAHA,FESCPRESIDENT – IACC www.accindia.org 1

  2. Elevated Resting Heart Rate • Accelerates production of atherosclerosis (Int J Cardiol 2008;126:302-12) • Associated with coronary plaque disruption (Circulation 2001;126:1477-82) • Framingham Study • progressive increase in all cause and cardiovascular mortality in relation to antecedent HR (Am Heart J 1987; 113:1489-94) • Continuous increase in death rates in survivors of Acute MI starting at HR > 70(J Am Coll Cardiol 2007;50:823-30) 2

  3. Beta-Adrenoceptors • Endogenous catecholamines • activate B-receptors • (Adenylate Cyclase) • Increased cAMP • Increased Ca++ influx Inotropic Chronotropic 3

  4. Beta Blockers (BB) • B1negative chronotropy and inotropy • AV conduction delay • Reduced atrial and ventricular arrythmias • B2Bronchoconstriction • Peripheral unopposed alpha constriction • Decrease glycogenolysis • (contribute to hypoglycemic events) • Other antagonize release of renin • reduces intraocular pressures 4

  5. Impact of BB • Acute MI • Norwegian Multicenter Study Group Timolol * • CAPRICORN † • ISIS-1 ‡ • CHF • COPERNICUS £ • MERIT-HF € 5

  6. Intolerence of BB • Side effects • Bronchoconstriction, AV delay, hypoglycemia • Weight gain, depression, fatigue • BB may not be tolerated in high enough doses to attain heart rates below 70bpm • Acute setting (Acute MI, or CHF), the negative inotropic effect could be deleterious • This has been shown in dogs (Eur Heart J (2004) 25 (7): 579-586 6

  7. If Current • The funny current is highly expressed in spontaneously active cardiac regions, such as the sinoatrial node (SAN, the natural pacemaker region), the atrio-ventricular node (AVN) and the Purkinje fibres of conduction tissue. • Particularly unusual, the funny current is a mixed sodium-potassium current, inward and slowly activating on hyperpolarization at voltages in the diastolic range (normally from -60/-70 mV to -40 mV). • When at the end of a sinoatrial action potential the membrane repolarizes below the If threshold (about -40/-50 mV), the funny current is activated and supplies inward current, which is responsible for starting the diastolic depolarization phase (DD); • By this mechanism, the funny current controls the rate of spontaneous activity of sinoatrial myocytes, hence the cardiac rate.

  8. If Current • Another unusual feature of If is its dual activation by voltage and by cyclic nucleotides. Cyclic adenosine monophosphate (cAMP) molecules bind directly to f-channels and increase their open probability. cAMP dependence is a particularly relevant physiological property, • Since it underlies the If –dependent autonomic regulation of heart rate. Sympathetic stimulation raises the level of cAMP molecules which bind to f-channels and shift the If activation range to more positive voltages; • This mechanism leads to an increase of the current at diastolic voltages and therefore to an increase of the steepness of DD and heart rate acceleration. • Parasympathetic stimulation (which acts to increase probability of potassium channels opening but decreases the probability of calcium channel opening) decreases the heart rate by the opposite action, that is by shifting the If activation curve towards more negative voltages.

  9. Ivabradine • Specifically binds the Funny channel • Reduces the slope for diastolic depolarization • Prolongs diastolic duration • Does not alter… • Ventricular repolarization • Myocardial contractility • Blood pressure 9

  10. Ivabradine Trials • Reduces atherosclerosis (Circ 2008;117:2377-87) • Decreases vascular oxidative stress • Improves endothelial function • Increases exertional tolerance and time to ischemia in patients with > 3 months angina (Circ 2003;107:817-23) • Non-inferior to Atenolol (Eur Heart J 2005;26:2529-36) • Exercise tolerance, time to angina or ischemia • Non-inferior to Amlodipine (Drugs 2007;67(3):393-405) 10

  11. MorBidity-mortality EvAlUation of The If inhibitor Ivabradine in patients with coronary disease and left ventricULar dysfunction BEAUTIFUL Trial

  12. 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.

  13. 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

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

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. Results

  21. 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.

  22. 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

  23. 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.

  24. 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.

  25. -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.

  26. 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.

  27. 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.

  28. 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.

  29. New Results In angina patients

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

  31. 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 Ivabradine 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.

  32. 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.

  33. 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.

  34. 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.

  35. 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.

  36. 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.

  37. Systolic Heart failure treatment withthe Ifinhibitor ivabradineTrial SHIFT Trial http://www.lancet.com published online August 29, 2010 DOI:10.1016/S0140-6736(10)61198-1

  38. Background • Elevated heart rate is associated with poor outcome in a number of cardiovascular conditions including heart failure • Heart rate remains elevated in many heart failure patients despite treatment by beta-blockers • Ivabradine is a novel heart rate-lowering agent acting by inhibiting the If current in the sino-atrial node • We hypothesized that the addition of ivabradine to recommended therapy would be beneficial in heart failure patients with elevated heart rate

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

  40. Multinational study Bulgaria Czech Republic Estonia Hungary Europe Germany Portugal Belgium Greece Spain Denmark Ireland Sweden Finland Italy Turkey France The Netherlands UK Latvia Lithuania Norway Poland Romania Russia Slovakia Slovenia Ukraine North America Canada Asia China Hong Kong India South Korea Malaysia South America Argentina Brazil Chili Australia 6505 patients, 37 countries, 677 centres

  41. Inclusion criteria • 18 years • Class II to IV NYHA heart failure • Ischaemic/non-ischaemic aetiology • LV systolic dysfunction (EF 35%) • Heart rate 70 bpm • Sinus rhythm • Documented hospital admission for worsening heart failure 12 months Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.

  42. 3.5 years Study design Ivabradine 7.5/5/2.5 mg bid according to Ivabradine 5 mg bid HR and tolerability Screening 7 to 30 days Matching placebo, bid Every 4 months D0 D14 D28 M4 Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.

  43. Study endpoints Primary composite endpoint • Cardiovascular death • Hospitalization for worsening heart failure Other endpoints • All-cause / CV / HF death • All-cause / CV / HF hospitalization • Composite of CV death, hospitalization for HF or non-fatal MI • NYHA class / Patient & Physician Global Assessment In total population and in patients with at least 50% target dose of beta-blockers Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.

  44. Patients and follow-up 7411 screened 6558 randomized 3268 to ivabradine 3290 to placebo Excluded: 26 Excluded: 27 3241 analysed 2 lost to follow-up 3264 analysed 1 lost to follow-up Median study duration: 22.9 months; maximum: 41.7 months

  45. Baseline characteristics

  46. Baseline characteristics

  47. Chronic HF background treatment Patients (%) 100 91 91 90 89 90 Ivabradine 84 83 80 Placebo 70 61 59 60 50 40 30 22 22 20 10 4 3 0 Beta-blockers ACEIs and/or Diuretics Aldosterone Digitalis ICD/CRT ARBs antagonists

  48. 90 80 70 60 50 40 30 20 10 0 Background beta-blocker treatment Patients (%) 100 Ivabradine 89 89 Placebo 56 56 26 26 At least 50% target daily dose Target daily dose BB at randomization

  49. Ivabradine Placebo Mean heart rate reduction Mean ivabradine dose: 6.4 mg bid at 1 month 6.5 mg bid at 1 year Heart rate (bpm) 90 80 80 75 75 70 67 64 60 50 0 2 weeks 1 4 8 12 16 20 24 28 32 Months

  50. Ivabradine Placebo Primary composite endpoint Ivabradine n=793 (14.5%PY) Placebo n=937 (17.7%PY) HR = 0.82 [95% CI 0.75-0.90]p<0.0001 Cumulative frequency (%) 40 - 18% 30 20 10 0 0 6 12 18 24 30 Months

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