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Heart rate a global target for cardiovascular disease and therapy along the cardiovascular disease continuum

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Heart rate a global target for cardiovascular disease and therapy along the cardiovascular disease continuum

  1. 1. Heart rate: A global target for cardiovascular disease and therapy along the cardiovascular disease continuum Prof Kyaw Soe Win MBBS, M.Med.Sc (Int.Med) MRCP (UK), FRCP (Edin), Dr Med Sc (Cardiology), Dip Med Ed, FAsCC, FAPSIC, FESC, FACC Fellowship in Interventional Cardiology ( Singapore) Senior Consultant Cardiologist, Mandalay General Hospital Hotel Marvel 15th May 2016
  2. 2. CONCLUSION • High resting heart rate is a predictor of mortality in a large variety of populations: • General population • Prehypertensive patients • Hypertensive patients • Stable CAD patients • ACS patients • Post-MI patients • Heart failure patients
  3. 3. Ivabradine indicated for CAD patients Symptomatic treatment of chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm: •in patients with HR > 70 bpm - In addition to beta-blockers - As an alternative to beta-blockers Indication approved by the European Medicines Agency, 02/2012
  4. 4. Ivabradine indicated for chronic heart failure • Ivabradine is indicated in chronic heart failure NYHA II to IV class with systolic dysfunction, in patients in sinus rhythm and whose heart rate is ≥ 70 bpm • In combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated Indication approved by the European Medicines Agency, 02/2012
  5. 5. Heart rate : the first rhythm in our life
  6. 6. per day: 80 x 60 min x 24 h = 115.200 beats per year: 42.048.000 beats 80 years: 3.363.840.000 beats ~300 mg ATP per beat ~ 30 kg ATP per day Heart Rate Reduction by 10 beats saves ~ 5 kg ATP per day Heart Rate – marker of metabolism Ferrari et al. EHJ 2008, 10(Suppl) F7-10.
  7. 7. The story of Hummingbird and Turtle Hummingbird: - HR = 600 bpm - lives 5 months Turtle: - HR = 6 bpm - lives 150 years Same number of heart beat in life: 500 million beats!
  8. 8. The Heart Rate and longevity throughout the whole animal kingdom • A study of birds and nonhibernating mammals showed a linear relationship between the resting HR and longevity • The only species to fall off the predicted line for longevity was men ( 30 yrs for stone aged men) • Life span of modern westernized man is about 80 yrs because of improved living standard and medical advances.
  9. 9. The higher Heart rate; The shorter life span
  10. 10. I. High resting heart rate and mortality in General population & Hypertensive patients II. Role of heart rate in development of atherosclerosis III. Role of heart rate in stable coronary artery disease IV. Role of heart rate in acute coronary syndrome V. Role of heart rate in postmyocardial infarction VI. Role of heart rate in chronic heart failure VII. New treatment option by slowing heart rate with Ivabradine Effect of Ivabradine on Morbi-mortality in CAD Effect of Ivabradine on Morbi-mortality in CHF Anti-ischemic efficacy of Ivabradine in patients already treated with beta blockers Outlines
  11. 11. I. High resting heart rate is an independent risk factor for mortality in General population & Hypertensive patients
  12. 12. Normal Population •Chicago Study- relationship between high HR and all-cause death and sudden CHD death¹. (1980) •Framingham study confirmed after 30 yrs follow-up. The relationship was stronger in men than women. (1987) •The results were confirmed by other three studies. Mensink GB et al. Eur Heart J 1997;18:1404-10. Tverdal A et al. Eur Heart J 2008;29:2772-81. Jouven X et al. Eur Heart J 2009;103:279-83. Resting Heart Rate as Prognostic indicators in non-Hypertensive subjects
  13. 13. Adapted from V. Aboyans et al.Adapted from V. Aboyans et al. Journal of Clinical EpidemiologyJournal of Clinical Epidemiology . 59 (2006) 547–558. 59 (2006) 547–558 Chicago Gas Company ‘80Chicago Gas Company ‘80 1,233 M1,233 M 15 y15 y >94 vs.>94 vs. <<60 bpm60 bpm 2.32.3 Chicago Heart Ass.Project ’80Chicago Heart Ass.Project ’80 33,781 M&W33,781 M&W 22 y22 y >>90 vs. <70 bpm90 vs. <70 bpm M: 1.6 W: 1.1 (ns)M: 1.6 W: 1.1 (ns) Framingham ‘93Framingham ‘93 4,530 M&W HTN4,530 M&W HTN 36 y36 y >100 vs. <60 bpm>100 vs. <60 bpm M: 1.5 W: 1.4 (ns)M: 1.5 W: 1.4 (ns) British Regional Heart ’93British Regional Heart ’93 735 M735 M 8 y8 y >90 vs.>90 vs. <<90 bpm90 bpm IHD death 3.3IHD death 3.3 Spandau ’97Spandau ’97 4,756 M&W4,756 M&W 12 y12 y Sudden deathSudden death 5.2 per 20 bpm5.2 per 20 bpm Benetos ’99Benetos ’99 19,386 M&W19,386 M&W 18.2 y18.2 y >100 vs. <60 bpm>100 vs. <60 bpm M: 2.2 W: 1.1 (ns)M: 2.2 W: 1.1 (ns) Castel ’99Castel ’99 1,938 M&W1,938 M&W 12 y12 y 5th vs. 3rd quintile5th vs. 3rd quintile M: 1.6 W: 1.1M: 1.6 W: 1.1 Cordis ’00Cordis ’00 3,257 M3,257 M 8 y8 y >>90 vs. <70 bpm90 vs. <70 bpm 2.02.0 Reunanen ’00Reunanen ’00 10,717 M&W10,717 M&W 23 y23 y M: 1.4 (>84 vs. <60)M: 1.4 (>84 vs. <60) W: 1.5 (>94 vs.<66)W: 1.5 (>94 vs.<66) Thomas ’01Thomas ’01 60,343 M HTN60,343 M HTN 14 y14 y >80 vs.>80 vs. <<80 bpm80 bpm <55y:1.5 >55y:1.3<55y:1.5 >55y:1.3 Matiss ’01Matiss ’01 2,533 M2,533 M 9 y9 y per 20 bpm: 1.5per 20 bpm: 1.5 >>90 vs. <60 bpm: 2.790 vs. <60 bpm: 2.7 Ohasama ‘04Ohasama ‘04 1,780 M&W1,780 M&W 10 y10 y M: 1.2 W: 1.1 (ns) per 5 bpmM: 1.2 W: 1.1 (ns) per 5 bpm Okamura ‘04Okamura ‘04 8,800 M&W8,800 M&W 16.5 y16.5 y per 11 bpm (1 SD) M: 1.3 W: 1.2per 11 bpm (1 SD) M: 1.3 W: 1.2 Jouven ’05Jouven ’05 5 713 M5 713 M 23 y23 y SSudden death from AMI 3.92 (>75 bpm)udden death from AMI 3.92 (>75 bpm) StudyStudy Population Follow-upPopulation Follow-up Cardiovascular mortality RRCardiovascular mortality RR Epidemiological studies on the relationshipEpidemiological studies on the relationship between HR and CV mortalitybetween HR and CV mortality (general population(general population and HTN)and HTN)
  14. 14. Cliquez pour modifier le style du titre du masque Cliquez pour modifier les styles du texte du masque Deuxième niveau Troisième niveau – Quatrième niveau – Cinquième niveau 15 Resting heart rate and all-cause mortalityResting heart rate and all-cause mortality The Framingham StudyThe Framingham Study Kannel WB et al Am Heart J. 1987;113:1489–1494. 0 10 20 30 40 50 60 Rate/1000subjects/year Men, 35-64 years Men, 65-94 years Heart Rate (bpm) 30-67 68-75 76-83 84-91 92-220 1987
  15. 15. Mensink and Hoffmeister. Eur Heart J. 1997;18:1404-1410 Resting heart rate and all-cause mortality forResting heart rate and all-cause mortality for 12 years in general population12 years in general population 0 5 10 15 20 25 Mortality% <60 60-70 70-80 80-90 >90 Heart rate (bpm) Women Men Men (n=1798) Women (n=2908) Aged 40-80 Years 1997
  16. 16. Cliquez pour modifier le style du titre du masque Cliquez pour modifier les styles du texte du masque Deuxième niveau Troisième niveau – Quatrième niveau – Cinquième niveau 17 12123 French men 0.70.7 0.750.75 0.80.8 0.850.85 0.90.9 0.950.95 11 11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414 1515 1616 1717 1818 1919 2020 2121 HR<60 bpmHR<60 bpm 60 HR 8060 HR 80 80 HR 10080 HR 100 HR>100HR>100 Follow-up (y) P=0.0001 ≤≤≤≤ ≤≤ ≤≤ Benetos, Hypertension. 33;44-52:1999 Resting heart rate and survival probabilityResting heart rate and survival probability inin French general population (men)French general population (men) 1999
  17. 17. High resting HR: an independent predictor of mortality in the Italian general population Seccareccia F, et al. Am J Public Health. 2001;91:1258-1263. 2001
  18. 18. High resting heart rate: an independent predictor of longer life in the elderly general population Benetos A, et al. Am J Geriatr Soc. 2003;51:284-285. 2003 Cohort study in 1407 men aged from 65 to 70 years, follow-up 18 years
  19. 19. HR: 66-73 bpm HR: 60-65 bpm HR: ≥78 bpm HR: <60 bpm High resting heart rate: an independent predictor of CV death in the Japanese general population Okamura T, et al. Am Heart J. 2004;147:1024-1032. 2004
  20. 20. Jouven et al. N Engl J Med. 2005;352:1951-1958 0.00.0 0.50.5 1.01.0 1.51.5 2.02.0 2.52.5 3.03.0 3.53.5 4.04.0 Relative riskRelative risk Resting heart rate (bpm)Resting heart rate (bpm) <60<60 286286 3333 1111 60-6460-64 191191 1414 99 65-6965-69 229229 2121 1313 70-7570-75 403403 2727 2323 >75>75 3434 2424 402402 Death from any causeDeath from any cause Non-sudden death from myocardial infarctionNon-sudden death from myocardial infarction Sudden death from myocardial infarctionSudden death from myocardial infarction Resting heart rate and risk of mortalityResting heart rate and risk of mortality in general populationin general population n=5713n=5713 2005
  21. 21. High resting heart rate: a marker of high CV risk in the Norwegian middle-aged population Aage T, et al. Eur Heart J. 2008;29:2772-2781. 2008
  22. 22. The Paris Prospective Study, general population, 5 713 men; 23-years follow-up Sudden death risk & Resting HR (general population) Jouven X, et al., N Engl J Med. 2005;352:1951-1958. 0.00.0 0.50.5 1.01.0 1.51.5 2.02.0 2.52.5 3.03.0 3.53.5 4.04.0 Relativerisk Resting heart rate (bpm) <60 60-64 65-69 70-75 >75 P<0.001 2.5 times
  23. 23. Resting heart rate and cardiovascularResting heart rate and cardiovascular deaths in in the type 2 diabetic patientsdeaths in in the type 2 diabetic patients 00 22 44 66 88 1010 1212 1414 1616 1818 2020 46-69 bpm46-69 bpm 70-75 bpm70-75 bpm 76-89 bpm76-89 bpm >90 bpm>90 bpm Cardiovasculardeath,(n)Cardiovasculardeath,(n) Linnemann B, Janka BU, Exp Clin Endocrinol Diabetes 2003;111:215-222
  24. 24. Heart Rate as a Predictor of Hypertension • A high heart rate has been shown to precede arterial stiffness¹ and also the development of hypertension upto 6 yrs later². • The high heart rate is a reflection of underlying increased sympathetic nerve activity, both day and night³. 1.Franklin SS. Arterial Stiffness and hypertension. Hypertension 2005;45:349-51. 2.Platini P, Dorigatti F, Zaetta V et al. Heart rate as a predictor of development of sustained hypertension in subjects screened for stage I hypertension: the HARVEST study. J Hypertens 2006;24:1873-80. 3.Hering D et al. Resting sympathetic outflow does not predict the morning blood pressure surge in hypertension. J Hypertens 2011;29:2381-6.
  25. 25. Kolloch et al., Eur Heart J. 2008;29:1327-34. INVEST study, 22 192 CAD patients; 2.7-year follow-up 50 20 10 40 30 0 60 0 3.5 4.0 4.5 3.0 2.5 2.0 1.5 1.0 0.5 Outcome (all-cause death, nonfatal MI, or nonfatal stroke) Hazard ratio Mean follow-up heart rate (bpm) ≤ 50 > 50 to ≤ 55 > 55 to < 60 > 60 to ≤ 65 > 65 to ≤ 70 > 80 to ≤ 85 > 85 to ≤ 90 > 70 to ≤ 75 > 75 to ≤ 80 > 90 to ≤ 95 > 95 to ≤ 100 > 100 Adverseoutcomeincidence(%) Estimatedhazardratio
  26. 26. Spectrum of CHD •Silent ischaemia •Stable Angina •Acute Coronary Syndrome (UAP,NSTEMI,STEMI) •Sudden Cardiac Death •Ischaemic Cardiomyopathy •Chronic Heart Failure
  27. 27. Evidences across Cardiovascular Continuum Remodeli ng Ventricular Dilation Chronic Heart Failure Myocardial Ischemia (angina) Atherosclerosis LVH Coronary Artery Disease Coronary Thrombosis Arrhythmi as End-Stage Heart Disease, Death Dyslipidemia Hypertensio n Diabetes Smoking Obesity Myocardial Infarction The Cardiovascular Continuum Dzau V et al. Circulation. 2006;114:2850-2870 Stable CAD & Normal EF
  28. 28. II. Role of heart rate in development of atherosclerosis
  29. 29. Variation of coronary flow and shear stress during the cardiac cycle 10 mm Hg DIASTOLE120 mm Hg Adapted from Giannoglou G et al. Int J Cardiol. 2008;126:302-312. SYSTOLE No flow (even retrograde subendocardial flow) No flow (even retrograde subendocardial flow) Coronary arterial flow (myocardial perfusion) Coronary arterial flow (myocardial perfusion) Increased shear stressIncreased shear stressLow and oscillatory shear stressLow and oscillatory shear stress Coronary arteries are prone to atherosclerosis
  30. 30. High heart rate accelerates coronary atherosclerosis progression Average coronaryAverage coronary stenosis (%)stenosis (%) Atherosclerotic area (mmAtherosclerotic area (mm22 )) Beere PA, et al. Science. 1984;226:180-182. 00 1010 2020 3030 4040 5050 6060 P<0.02P<0.02 P<0.05P<0.05 High HRHigh HR Low HRLow HR 00 0.10.1 0.20.2 0.30.3 0.40.4 0.50.5 Baboon Cholesterol- rich diet High HRHigh HR Low HRLow HR
  31. 31. Perski A, et al. Am Heart J. 1988;116:1369-1373. Heart rate and coronary atherosclerosis Minimum heart rate (bpm) Coronaryatherosclerosisscore(%) 50 0 4 1 2 3 40 60 70 80 90 r= 0.70 P<0.002 16 MI survivors, 6-month follow-up; 2 coronary angiographies; 24-hour ECG
  32. 32. III. Role of heart rate in stable coronary artery disease Heart rate & ischaemia
  33. 33. Resting Heart Rate and stable CHD In 24913 patients with suspected or proven CHD, followed up for 15 yrs, a high resting HR > 83 bpm was predictive of total and cardiovascular mortality, with optimal survival at HR <62 bpm. Diaz A et al. Eur Heart J 2005;26:967-74
  34. 34. HR <62 bpm HR >78 bpm
  35. 35. Elevated Heart RateElevated Heart Rate IschemiaIschemia Major CV eventsMajor CV events Increased OIncreased O22 demanddemand Decreased supplyDecreased supply Progression ofProgression of atherosclerosisatherosclerosis PlaquePlaque rupturerupture Short term Long term Atherosclerosis Vascular damageVascular damage Role of elevated HR in the pathophysiology of CAD
  36. 36. Increased heart rate worsens ischaemia Increased workload Increased O2 demand Decreased O2 supply IschIschaaemiaemia Decreased diastolic time Increased heart rate
  37. 37. Heart rate is associated with increased risk of majorHeart rate is associated with increased risk of major cardiovascular events in stable CAD eventscardiovascular events in stable CAD events Rambihar S, et al. Circulation. 2010;122(suppl. 21): abstract12667 The ONTARGET/TRANSCEND trial (n=31531) Cumulative incidence rates Q4 71-78 bpmQ4 71-78 bpm Q5Q5 >> 79 bpm79 bpm Q3 65-70 bpmQ3 65-70 bpm Q2 59-64 bpmQ2 59-64 bpm Q1Q1 << 58 bpm58 bpm 0 0.05 0.10 0.15 0.20 0.25 Years of follow-up 0 1 2 3 4 5
  38. 38. Heart rate as a major determinant of ischemia 1. Andrews TC et al. Circulation.1993;88:90-100. 00 44 88 1212 1616 2020 %% <60<60 60-6960-69 70-79 80-8970-79 80-89 >89>89 Heart rate at rest, bpmHeart rate at rest, bpm XX 22 timestimes Ischemia
  39. 39. Heart Rate as a predictor of coronary events Aronov W. S et al. Am J Cardiol. 1996;78:1175-1176 New coronaryNew coronary events, %events, % <60<60 61-7061-70 71-8071-80 81-9081-90 91-10091-100 >100>100 00 1010 2020 3030 4040 5050 6060 7070 XX 22 timestimes Mean heart rate on 24-Hour Ambulatory ECG, bpm N= 1 311 CHD patients with 48-months follow-up P<0.0001 5 bpm of HR = 1.14 incidence of coronary events
  40. 40. Increased heart rate worsens ischaemia Increased workload Increased O2 demand Decreased O2 supply IschIschaaemiaemia Decreased diastolic time Increased heart rate
  41. 41. Lowering heart rate relieves ischaemia Decreased workload Decreased O2 demand Preserved O2 supply IschIschaaemiaemia Increased diastolic time Decreased heart rate
  42. 42. Angina Severity and Mortality 0 2 4 6 8 10 12 Severe Moderate Mild Minimal SAQ Angina Frequency Score Spertus JA, et al. Circulation. 2002;106:43-9 1yearmortalityrate SAQ=Seattle Angina Questionnaire
  43. 43. 39% of patients receiving β-blockers had a heart rate above 70 bpm Patients (%) in different HR according to HR lowering treatment at baseline (n=2 005) from The Euro Heart Survey Inadequate control of heart rate in patients with stable angina 00 55 1010 1515 2020 2525 3030 3535 ≤≤6262 63-7063-70 71-7671-76 77-8277-82 CCBsCCBs BBsBBs Resting HR (bpm)Resting HR (bpm) ≥≥8383 Daly C et al.Daly C et al. Postgrad Med JPostgrad Med J 2010;86:212-217.2010;86:212-217.
  44. 44. A Diaz et al. EHJ 2005; 26: 976-74
  45. 45. IV. Role of heart rate in acute coronary syndrome
  46. 46. Resting Heart Rate and ACS In 139194 patients with NSTE-ACS, there was J-shaped relationship between the resting HR and all-cause mortality, with HR < 50 bpm being associated with increased mortality ( whether or not a b blocker was present). Bangalore S et al. Eur Heart J 2010;31:552-60
  47. 47. High Heart Rates are Predictive of Coronary Plaque Ruptures Heidland UE, Strauer BE. Circulation. 2001;104:1477-1482. AS-ct11-0706
  48. 48. Higher heart rate on admission increases risk of mortality in patients with acute MI Hjalmarson A, et al. Am J Cardiol. 1990;65:547-553. • n = 1,807 AMI • multi-centre • mortality: in-hospital & post discharge • with / without heart failure
  49. 49. HR<96HR<96 96-12 113-13396-12 113-133 >133>133 Death/MI at 30 daysDeath/MI at 30 days Death/MI at 1 yearDeath/MI at 1 year Age (years)Age (years) Heart rate (bpm)Heart rate (bpm) <70<70 00 70–8970–89 77 90–10990–109 1313 110–149110–149 2323 150–199150–199 3636 >200>200 4646 Systolic BP (mmHg)Systolic BP (mmHg) Creatinine (mg/dL)Creatinine (mg/dL) Killip classKillip class Cardiac arrest atCardiac arrest at admission Elevatedadmission Elevated cardiac markers ST-cardiac markers ST- segment deviationsegment deviation GRACE scoreGRACE score for risk prediction in patients with ACSfor risk prediction in patients with ACS Goncalves P. European Heart Journal (2005) 26, 865–872 3030 2525 2020 1515 1010 55 00 GRACE Heart rate
  50. 50. V. Role of heart rate in Postmyocardial infarction
  51. 51. All cause mortality Sudden cardiac death HR variability LVEF HR mean Sensitivity Specificity Copie X, et al JACC 1996;27:270-6. • n = 579 • Heart rate and LVEF at discharge • 2-year follow-up • HR better predictor of mortality than LVEF Heart rate better predictor of post-MI mortality than LVEF In predischarge patients with MI, both 24 hr mean HR and HR variability were predictors of mortality over next 2 yrs.
  52. 52. Kjekshus JK. Eur Heart J. 1985;6:A29. Am J Cardiol 1986;57:43F Early intervention AMI size r=0.97 Post AMI Mortality r=0.79 Reinfarction r=0.59 R=0.79 P<0.005 Reduction of heart rate prolongs life post MI In postmyocardial infarction period, survival was closely related to the reduction of HR on b-blockers.
  53. 53. Propranolol Atenolol Timolol Metoprolol Metoprolol Propranolol -4 -8 -12 -16 -20 Reduction in heart rate (min-1 ) -30 -20 -10 Reduction in infarct size (%) Kjekshus JK. Am J Cardiol. 1986;57:43F-49F. Lowering heart rate reduces infarct size in MI
  54. 54. Heart rate at discharge & 6-month mortality (GISSI-3) Zuanetti et al. Eur Heart J. Supplements 1999, Vol. 1 (Suppl H):H52-H57 2525 1515 55 00 %% <60 bpm 60-80 bpm60-80 bpm 81-100 bpm81-100 bpm >100 bpm 1.91.9 3.93.9 9.39.3 20.220.2 1010 2020 n=11020 6-month mortality 10 times
  55. 55. HR loweringHR lowering & reduction in& reduction in cardiac deathscardiac deaths (post-MI patients)(post-MI patients) Cucherat M et al. Eur Heart J. 2006, 27(Abstract Suppl):590. 10 bpm HR reduction =10 bpm HR reduction = -- 2626% cardiac death% cardiac death Meta-regression of 12 controlled studiesMeta-regression of 12 controlled studies ∆∆ HRHR (bpm)(bpm) Relativerisk(log) 0.1 0.2 0.5 1.0 2.0 -5 -10 -15 -200 P<0.001P<0.001
  56. 56. VI. High resting heart rate in chronic heart failure
  57. 57. HR and one-year mortality in CIBIS-II trial Lechat P, et al. Circulation. 2001;13:1428-33. High heart rate is deleterious in clinical heart failure 6 2 0 One-year mortality (%) ≤ 72 4 8 10 12 14 ≤ 84 > 84 Heart rate (bpm)
  58. 58. High resting heart rate is an independent predictor of death in patients with heart failure Lechat P. CIBIS II. Circulation. 2001:103:1428-1433.
  59. 59. Trials that shows heart rate lowering reduces mortality in CHF -18 -16 -14 -12 -10 -8 -6 -4 -2 0 2 4 6 8 10 -100 -80 -60 -40 -20 0 20 40 60 XAMOTEROL PROFILE PROMISE VHeFT (HDZ/ISDN)SOLVD CONSENSUS ANZ VHeFT (prazosin) US CARVEDILOL BHAT CIBIS NOR TIMOLOL MOCHA GESICA Change in mortality (%) Change in heart rate (bpm) Kjekshus et al. Eur Heart J. 1999 (suppl), H64-H69
  60. 60. CHARM program: baseline heart rate & outcome Castagno D. J Am Coll Cardiol. 2012;:59. 2012:1785–95 Resting heart rate predicts outcomes in heart failure, regardless of LVEF or beta-blocker use Heart rate tertile T1 mean 60 T2 mean 72 T3 mean 86
  61. 61. American College of Cardiology / American Heart Association ACC/AHA guidelines. 2002.
  62. 62. Lowering heart rate ???new treatment option A key objective to save lives in both CAD & heart failure
  63. 63. With WHAT & HOW we should lower it?
  64. 64. Heart rate lowering withHeart rate lowering with beta-blockersbeta-blockers && Calcium channel blockersCalcium channel blockers 00 PlaceboPlaceboPropranololPropranolol DiltiazemDiltiazem22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424 5050 6060 7070 8080 9090 Mean Heart Rate (bpm)Mean Heart Rate (bpm) xx xx xx xx xx xx xx xx xx xx xx 44 33 22 11 Daily frequency of ischemic episodesDaily frequency of ischemic episodes Stone PH, Circulation 1990;82:1962-1972
  65. 65. Sir James Black British pharmacologist Discovered propranolol in 1960 and brings wonderful benefits to coronary patients Earned Noble Prize in 1980 Passed away in 2010 at the age of 85
  66. 66. Effects of beta-blockers = Reduces heart rate = Reduces LV contraction = Reduces conduction = Reduces blood pressure = Prevents coronary vasodilatation during exercise
  67. 67. Limitation of BETA-BLOCKERSLimitation of BETA-BLOCKERS Hard to reach target doseHard to reach target dose Hypertriglyceridemia Atrio-ventricular block 2 and 3 Decreased HDL cholesterol Sexual dysfunction Fatigue Insomnia COPD Asthma Diabetes Rebound effect
  68. 68. Are there anything more than beta-blockers?
  69. 69. Cliquez pour modifier le style du titre du masque Cliquez pour modifier les styles du texte du masque Deuxième niveau Troisième niveau – Quatrième niveau – Cinquième niveau 78 Lowering heart rate ???new treatment option A key objective to save lives in both CAD & heart failure with Ivabradine:
  70. 70.  Pure heart rate reduction  Preserves blood pressure, myocardial contractility and coronary vasodilatation  Major antianginal efficacy  Reduces CV events (BEAUTIFUL)  Additive efficacy with beta-blockers  Dosage: 5mg BD to 7.5mg BD The first selective and specific If inhibitor Ivabradine
  71. 71. Ivabradine: pure heart rate reduction If inhibition reduces the diastolic depolarization slope and thereby lowers heart rate RR Pure heart rate reduction 0 mV -40 mV -70 mV Thollon C, et al. Brit J Pharmacol. 1994;112:37-42. closed open closed Ivabradine • If current is an inward Na+ /K+ current that activates pacemaker cells of the SA node • Ivabradine – Selectively blocks If in a current- dependent fashion – Reduces slope of diastolic depolarization, slowing HR
  72. 72. 0 -5 -10 -15 ∆ bpm Ivabradine (mg) 5 bid 7.5 bid Atenolol (mg) 50 od 100 od n=286n=595 n=300 Heart rate reduction Ivabradine vs Atenolol Tardif JC, et al. Eur Heart J. 2005;26:2529-2536. -15 bpm -16 bpm
  73. 73. -40 -30 -20 -10 0 10 40 50 60 70 80 90 100 110 120 Baseline HR (bpm) ∆HFfrobaseline(bpm) 5 mg bid 7.5 mg bid Heart Rate Reduction by Ivabradine is Dependent on Baseline Heart Rate (n=720): Safety Relevance!
  74. 74. Anti-ischemic efficacy of Ivabradine compared to beta blockers INITIATIVE
  75. 75. 25 mg od placebo ate 50 mg od (n=307) iva 5 mg bid (n=315) iva 5 mg bid (n=317) placebo 50 mg od placebo Atenolol 100 mg od Ivabradine 7.5 mg bid Ivabradine 10 mg bid M1 ETT Randomization (n=939) M4 ETT Wash-out 2-7 days Run-in 7 days Run-out 14 days 1 month 3 months Pre-selection (n=1789) The INITIATIVE study Mo ETT Tardif J-C, et al. Eur Heart J. 2005;26:2529-2536. The clinical efficacy of Ivabradine Vs beta-blockers INITIATIVE
  76. 76. 00 11 22 33 44 AAtenololtenolol 100 mg100 mg Reduction in number of angina attacksReduction in number of angina attacks (after 4-month treatment)(after 4-month treatment) Baseline Baseline Antianginal efficacy of Ivabradine IvabradineIvabradine 7.5 mg7.5 mgIvabradineIvabradine 7.5 mg7.5 mg Tardif JC, et al. Eur Heart J. 2005;26:2529-2536. Number/weekNumber/week - 70%- 72% INITIATIVE
  77. 77. Tardif JC. Drugs of Today. 2008;44:171-181. Increase in exercise capacity (total exercise duration) related to 1 beat of heart rate reduction Change in TED (sec) at 4 months per 1 beat of HR reduction Ivabradine 7.5 mg Preserved exercise-induced coronary vasodilation? Reduced coronary vasomotor tone? Prolonged diastolic duration and myocardial perfusion? Lack of negative inotropic effect? Lack of lower limb arterial vasoconstriction INITIATIVE x 2 Efficiency of exclusive heart rate reduction
  78. 78. Atenolol 100 mg od better Ivabradine 7.5 mg bid better 0- 35 sec +35 sec Total exercise duration Time to limiting angina Time to angina onset Time to 1-mm ST-segment depression ETT parameters at trough of drug activity after 4 months Equivalence limits P<0.0001 P for non-inferiority P<0.0001 P<0.0001 P<0.0001 Clinical Efficacy of ivabradine versus atenolol in the INITIATIVE study Tardif JC, et al. Eur Heart J. 2005;26:2529-2536. INITIATIVE
  79. 79. INITIATIVE Key messages 1. Ivabradine is as effective as Atenolol 100 mg 2. For 1 beat of HR reduction, Ivabradine provides 2 times > exercise capacity than Atenolol (because of its pure heart rate reduction preserving contractility, coronary vasodilation, BP) INITIATIVE
  80. 80. Anti-ischemic efficacy of Ivabradine in patients already treated with beta blockers (1 Tardif JC, Ponikowski P, Kahan T; ASSOCIATE study investigators. Efficacy of the If current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4 month, randomized, placebo-controlled trial. Eur Heart J. 2009;30:540-548
  81. 81. Main inclusion criteria • Patients with documented CAD with a history of chronic stable angina • Already on atenolol 50mg od or other BB (equivalent dosage) • HR>60bpm • Positive exercise tolerance test (1 Tardif JC, Ponikowski P, Kahan T; ASSOCIATE study investigators. Efficacy of the If current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4 month, randomized, placebo-controlled trial. Eur Heart J. 2009;30:540-548
  82. 82. Ivabradine reduces heart rate in patients already receiving β-blockers 54 56 58 60 62 64 66 68 Baseline M2 M4 IvabradineIvabradine 5 mg bid5 mg bid Ivabradine 7.5 mg bid (90% of pts) 67 60 (- 7 bpm) 66 66 - 9 bpm Ivabradine + atenolol Placebo + atenolol IvabradineIvabradine 7.5 mg bid7.5 mg bid Tardif JC, et al. Eur Heart J. 2009;30:540-548. Heart rate (bpm) 58
  83. 83. Ivabradine + atenolol Placebo + atenolol 0 10 20 30 40 50 60 Total exercise duration Time to limiting angina Time to angina onset Time to 1mm ST depression P<0.001 P<0.001 P<0.001 P<0.001 Ivabradine increases all ETT parameters in patients already receiving BBs Tardif JC, et al. Eur Heart J. 2009;30:540-548. Change in ETT criteria* (s) at 4 months + 3 times+ 3 times “This study represents the most compelling single demonstration of the benefit of any combination of antianginal drugs published to date” Eur Heart journal “This study represents the most compelling single demonstration of the benefit of any combination of antianginal drugs published to date” Eur Heart journal Tardif JC, et al. Eur Heart J. 2010;31(suppl. 1):198 (abstract 1335).
  84. 84. Ivabradine PlaceboPlacebo Asymptomatic 3.0%3.0% 0.5%0.5% Symptomatic 1.1%1.1% 0.3%0.3% Safety of ivabradine in combination with beta-blocker Bradycardia Tardif JC, et al. Eur Heart J. 2009;30:540-548. Withdrawal due to sinus bradycardia 0.9%0.9% 0%0%
  85. 85. Key messages • First compelling benefits of improvements in exercise parameters in combination with beta-blockers • Safe in combination with beta-blockers •Reinforces Ivabradine’s baseline dependent HR reduction (Baseline HR: 67 bpm, drop by 9) •From 60 bpm, all CAD patients receving Ivabradine should be up-titrated to 7.5 mg (87% pts = 7.5 mg)
  86. 86. In combination with BBs, Ivabradine provides the best benefits compared to other antianginals Tardif JC, et al. Eur Heart J. 2008;29(suppl):386 (abstract 2380). Klein meta-analysis - CARISA + Ivabradine*+ Ivabradine* Change of time to 1- mm ST depression - mean difference from placebo (s) 0 10 20 30 40 P<0.001 b-blockers + Calcium+ Calcium antagonists**antagonists** P=0.21 + Ranolazine**+ Ranolazine** P=NS + Nicorandil or+ Nicorandil or molsidomine ormolsidomine or L-A nitratesL-A nitrates No dataNo data At trough of drug activity *Standard Bruce Protocol **Modified Bruce
  87. 87. -70 -60 -50 -40 -30 -20 -10 0 O verall W om en Previous M I* Previous PTC A*Previous C ABG *D iabetes Asthm a/C O PD *PVD * Age >65 years Antianginal efficacy of ivabradine across all subpopulations of angina patients Tendera M, et al. Cardiology. 2009;114:116-125. 5 randomized trials including 24 25 stable angina pts 51% to 70% reductions in frequency of Angina Attacks51% to 70% reductions in frequency of Angina Attacks Change in angina attacks from baseline (%)
  88. 88. Does It Work in Clinical Practice?Does It Work in Clinical Practice? ADDITIONSADDITIONS STUDYSTUDY
  89. 89. • 2,2302,230 StableStable anginaangina patients, HRpatients, HR > 60 bpm> 60 bpm •Insufficiently controlled with BB aloneInsufficiently controlled with BB alone •Change in medical treatment (intolerance or insuf efficacy)Change in medical treatment (intolerance or insuf efficacy) • On top ofOn top of BBBB • 4 months4 months treatmenttreatment • Parameters recordedParameters recorded 1.Heart Rate 2.Angina attacks 3.Nitrate consumption 4.Tolerance 5.QOL Design of addition studyDesign of addition study Werdan K, et al. Clin Res Cardiol. 2012.
  90. 90. Werdan K, et al. Clin Res Cardiol. 2012. Multicenter, prospective study in 2330 patients with stable angina pectoris Angina attacks 4 5 3 2 1 0 1.7 0.6 0.3 Baseline 1 Month 4 Months P<0.001 for all differences Short-acting nitrates 4 6 2 0 2.3 0.8 0.4 Baseline 1 Month 4 Months P<0.001 for all differences Ivabradine in combination with beta-blockersIvabradine in combination with beta-blockers improves symptoms in angina patientsimproves symptoms in angina patients
  91. 91. Effect of Ivabradine on Morbi-mortality in CAD Angina Evidences of Ivabradine
  92. 92. MorBidity-mortality EvAlUation of The If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction MorBidity-mortality EvAlUation of The If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction
  93. 93. Primary objective 1. Effects of Ivabradine on the prevention of cardiovascular events in patients with CAD and LV systolic dysfunction 2. To examine the effects of elevated HR (≥ 70 bpm) in patients with CAD and LV systolic dysfunction on cardiovascular events
  94. 94. Inclusion criteria • Documented coronary artery disease • Documented LV systolic dysfunction (EF < 40%) • Sinus rhythm and resting heart rate ≥ 60 bpm K. Fox et al. Am Heart J. 2006;152:860-866
  95. 95. Study design Visits 3 YEARS K. Fox et al. Am Heart J. 2006;152:860-866 Ivabradine 5 mg  7.5 mg bid placebo On top of recommended therapy
  96. 96. Values in parentheses are standard deviations PlaceboPlacebo ivabraineivabraine Male, %Male, % 8383 8383 8383 Age, yearsAge, years 65.0 (8.4)65.0 (8.4) 65.3 (8.5)65.3 (8.5) 65.2 (8.5)65.2 (8.5) NumberNumber 54385438 54795479 10 91710 917 Resting heart rate, bpmResting heart rate, bpm 71.6 (9.9)71.6 (9.9) 71.5 (9.8)71.5 (9.8) 71.6 (9.9)71.6 (9.9) Systolic BP, mm HgSystolic BP, mm Hg 127.9 (15.5)127.9 (15.5) 128.1 (15.7)128.1 (15.7) 128.0 (15.6)128.0 (15.6) Diastolic BP, mm HgDiastolic BP, mm Hg 77.5 (9.2)77.5 (9.2) 77.4 (9.3)77.4 (9.3) 77.5 (9.3)77.5 (9.3) AllAll LV ejection fraction, %LV ejection fraction, % 32.3 (5.5)32.3 (5.5) 32.4 (5.5)32.4 (5.5) 32.4 (5.5)32.4 (5.5) Lancet, online August 31 2008 Baseline characteristics
  97. 97. Optimal preventive therapyOptimal preventive therapy Study Therapy Aspirin or antithrombotic (%) Statins (%) BB (%) RAS agents (%) TRACE 1995 AMI + LVD Trandolapril 92 – 17 CIBIS II 1999 CHF Bisoprolol 40 – 96 MERIT HF 1999 CHF Metoprolol 46 25 89 HOPE 2000 High CV risk Ramipril 75 28 39 COPERNICUS 2001 CHF Carvedilol – –  97 CAPRICORN 2001 AMI + LVD Carvedilol 86 – 98 EUROPA 2003 Stable CAD Perindopril 92 58 62 COMET 2003 CHF Metoprolol/carvedilol 35 20 92 SENIORS 2005 Elderly CHF Nebivolol 43 20 82 COURAGE 2007 Stable CAD Optimal medical therapy Revascularization 95 89 89 65         REACH CAD Registry 93 76 62 8 BEAUTIFUL 2008 CAD + LVD ivabradine 94 74 87 90 Patients
  98. 98. Mean HR reduction in overall population Heart rate (bpm) 50 60 70 80 Follow-up (days) 0 15 30 90 180 360 540 720 Placebo Ivabradine 69 61 69 64 72 Lancet, online August 31 2008 -5 bpm-5 bpm HR as inclusionHR as inclusion ≥ 60 bpm AverageAverage 71 bpm71 bpm
  99. 99. Mean HR reduction (Patients with baseline HR ≥ 70 bpm) Heart rate (bpm) 65 75 73 66 79 50 60 70 80 Follow-up (days) 0 15 30 90 180 360 540 720 Placebo Ivabradine Mean dose of Ivabradine 6.64 mg bid Lancet, online August 31 2008 -7 bpm-7 bpm
  100. 100. Effect of ivabradine on the primary endpoint (overall population) Effect of ivabradine on the primary composite endpoint (HR ≥ 70 bpm)
  101. 101. Effect of ivabradine in patients with HR ≥70 bpm coronary revascularization hospitalization for MI
  102. 102. Heart rate as a predictor of CARDIOVASCULAR DEATH Fox et al. Lancet. 2008;372:817-21. + 34% REVASCULARIZATION +38% HOSPITALIZATION FOR HF HOSPITALIZATION FOR MI + 53% + 46%
  103. 103. 0.11431%0.69Fatal MI 0.02322%0.78Fatal and nonfatal MI or unstable angina 0.01630%0.70Coronary revascularization 0.00923%0.77Fatal and nonfatal MI, unstable angina or revascularization 0.00136%0.64Fatal and nonfatal MI P valueRisk reduction Hazard ratio Predefined end point Ivabradine reduces coronary risk in stable coronary patients with HR ≥ 70 bpm Fox et al .Lancet. 2008;372:807-816.
  104. 104. Secondary prevention of myocardialSecondary prevention of myocardial infarction in stable CADinfarction in stable CAD NNT-1 Number needed to treat to prevent one event per 1 year (NNT-1) Study Event ACE inhibitorsACE inhibitors StatinsStatins Ivabradine Scandinavian Simvastatin Survival Study (4S)1 63 patients Major coronary event (coronary death and non-fatal MI) HOPE2 229 patientsFatal and non-fatal MI BEAUTIFUL study3 93 patientsFatal and non-fatal MI 1- Kjekshus J. Am J Cardiol.1995;76:64C-68C. 2-HOPE Investigators N Eng J Med. 2000;342:145-153 3- Fox K, et al. Lancet. 2008;372:807-816.
  105. 105. RanolazineRanolazine TrimetazidineTrimetazidine ββ-Blockers-Blockers Calcium antag.Calcium antag. NitratesNitrates NicorandilNicorandil Ivabradine Improved time to onset of ST-segment depression ++ ++ ++ ++ ++ ++ + Decrease in anginal episodes ++ ++ ++ ++ ++ ++ + Improved total exercise duration ++ ++ ++ ++ ++ ++ + Reduced revascularization NANA –– –– ++ –– NANA + Prevention of MI NANA –– –– –– –– –– + Improved survival NANA –– –– –– –– –– –– Ivabradine - the only antianginal treatment to reduce myocardial infarction in stable coronary patients Fox K, et al. Lancet. 2008;372:807-816 Adapted from ESC Guidelines on stable angina 2006
  106. 106. New evidence from ESC’09 Breaking News A subgroup analysis in patients with limiting anginalimiting angina at baseline A subgroup analysis in patients with limiting anginalimiting angina at baseline AnginaAngina
  107. 107. Patients with angina and follow-up 1507 randomized with angina 734 to Ivabradine 773 to placebo 773 analyzed734 analyzed 12 138 screened 10 917 randomized Angina
  108. 108. In patients with angina as limiting symptoms at entry, ivabradine independently improved the primary composite endpoint reduced hospitalization for fatal and non-fatal MI Angina substudy results Angina
  109. 109. Ivabradine reduces primary composite end point HR (95% CI), 0.76 (0.58–1.00), P=0.05 Years HR (95% CI), 0.69 (0.47–1.01), P=0.06 Years 0 5 10 15 20 25 30 0.5 1 1.5 2 0 5 10 15 20 25 30 0.5 1 1.5 2 Placebo Ivabradine Placebo Ivabradine *Cardiovascular mortality or hospitalization for fatal and nonfatal MI or HF Fox K, et al. Eur Heart J. 2009; 30:2337-2345 . Event rate (%) Event rate (%) -24% -31% All patients with limiting angina Patients with limiting angina & HR > 70 bpm
  110. 110. Placebo Ivabradine HR (95% CI), 0.27 (0.11–0.66), P=0.002 Years Placebo Ivabradine HR (95% CI), 0.58 (0.37–0.92), P=0.021 Years 0 5 10 15 0.5 1 1.5 2 0 5 10 15 0.5 1 1.5 2 Ivabradine reduces hospitalization for MI * Fatal and nonfatal events Fox K, et al. Eur Heart J. 2009; 30:2337-2345 . Event rate (%) Event rate (%) - 42% -73% Angina All patients with limiting angina Patients with limiting angina & HR > 70 bpm
  111. 111. x x Bradycardia Hypotension Negative inotropic effect Peripheral vasoconstriction Increase coronary resistance Bronchospasm Decrease to insuline response Fatigue Depression Sleep disturbances Erectile dysfunction Lower limbs oedema Constipation Visual effects x x x x x x x x x x x x +/- x x x x x x BB CCB Ivabradine Ivabradine free from the side-effects of the β- blockers and Calcium-channel-blockers
  112. 112.  In Angina patients, Ivabradine reduces  hospitalization for fatal and non-fatal MI by - 42% - 73% in patients HR > 70 bpm Fox K, et al. Cardiology. 2008;110:271-282.  CAD patients with heart rate >70 BPM has higher risk of  CV mortality by +34% hospitalization for HF by +53% hospitalization for MI by +46% (compared to HR < 70 BPM) SUMMARY
  113. 113.  In CAD patients with LVD, a HR of ≥ 70 bpm predicts an adverse outcome for CV death, hospitalization for HF or MI and revascularization Key Messages  Ivabradine is well tolerated (2.7% symptomatic bradycardia and 0.5% visual symptoms)  Ivabradine ( HR 7 bpm) improves coronary outcomes in patients with HR ≥70 bpm
  114. 114. Effect of Ivabradine on Morbi-mortality in AMI Evidences of Ivabradine
  115. 115. Systolic Heart failure treatment with the If inhibitor ivabradine Trial Systolic Heart failure treatment with the If inhibitor ivabradine Trial
  116. 116. Primary objective To evaluate whether theTo evaluate whether the IIff inhibitor ivabradineinhibitor ivabradine improvesimproves cardiovascular outcomescardiovascular outcomes in patients within patients with moderate to severemoderate to severe chronic heart failurechronic heart failure (LVEF(LVEF ≤≤ 35%)35%) && Heart rateHeart rate ≥≥70 bpm70 bpm,, on top of best recommended therapyon top of best recommended therapy To evaluate whether theTo evaluate whether the IIff inhibitor ivabradineinhibitor ivabradine improvesimproves cardiovascular outcomescardiovascular outcomes in patients within patients with moderate to severemoderate to severe chronic heart failurechronic heart failure (LVEF(LVEF ≤≤ 35%)35%) && Heart rateHeart rate ≥≥70 bpm70 bpm,, on top of best recommended therapyon top of best recommended therapy
  117. 117. EUROPE Germany Portugal Belgium Greece Spain Denmark Ireland Sweden Finland Italy Turkey France The Netherlands UK Bulgaria Czech Republic Estonia Hungary South America Argentina Brazil Chili North America Canada ASIA China Hong Kong India South Korea Malaysia Australia Latvia Lithuania Norway Poland Romania Russia Slovakia Slovenia Ukraine The largest Heart Failure trial 6505 patients, 376505 patients, 37 countriescountries, 677, 677 centrescentres ASIA : 520 ptsASIA : 520 pts
  118. 118.  ≥18 years  NYHA Class II to IV heart failure (ischemic or non-ischemic)  LV systolic dysfunction (EF ≤≤35%)  Heart rate ≥70 bpm with sinus rhythm  Documented hospital admission for worsening heart failure ≤12 months Inclusion criteria Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.
  119. 119. Study endpoints  Cardiovascular death  Hospitalization for worsening heart failure Primary composite endpoint 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-blockersIn total population and in patients with at least 50% target dose of beta-blockersIn total population and in patients with at least 50% target dose of beta-blockersIn 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.
  120. 120. Baseline characteristics IvabradineIvabradine 32413241 PlaceboPlacebo 32643264 Mean age, yMean age, y 60.760.7 60.160.1 Male, %Male, % 7676 7777 Ischaemic aetiology, %Ischaemic aetiology, % 6868 6767 NYHA II, %NYHA II, % 4949 4949 NYHA III/IV, %NYHA III/IV, % 5151 5151 Previous MI, %Previous MI, % 5656 5656 Diabetes, %Diabetes, % 3030 3131 Hypertension, %Hypertension, % 6767 6666 Swedberg K, et al. Lancet. 2010;online August 29.
  121. 121. Mean heart rate reduction 70% of patients70% of patients on ivabradine 7.5 mg bidon ivabradine 7.5 mg bid 0 2 weeks 1 4 8 12 16 20 24 28 32 MonthsMonths 90 80 70 60 50 67 75 75 80 64 Heart rate (bpm)Heart rate (bpm) Placebo Ivabradine Swedberg K, et al. Lancet. 2010;online August 29. - 8 bpm- 8 bpm
  122. 122. 0 6 12 18 24 30 40 30 20 10 0 Primary composite endpoint (CV death or hospital admission for worsening HF) - 18% Cumulative frequency (%)Cumulative frequency (%) Placebo Ivabradine HR = 0.82 (0.75–0.90) P < 0.0001 Swedberg K, et al. Lancet. 2010;online August 29. MonthsMonths
  123. 123. 0 6 12 18 24 30 30 20 10 0 Hospitalization for HF - 26% Placebo Ivabradine HR = 0.74 (0.66–0.83) P < 0.0001 Swedberg K, et al. Lancet. 2010;online August 29. MonthsMonths Cumulative frequency (%)Cumulative frequency (%)
  124. 124. Death from heart failure - 26% 0 6 12 18 24 30 10 5 0 HR = 0.74 (0.58–0.94) P = 0.014 Placebo Ivabradine Swedberg K, et al. Lancet. 2010;online August 29. MonthsMonths Cumulative frequency (%)Cumulative frequency (%)
  125. 125. 0 6 12 18 24 30 30 20 10 0 Cardiovascular death Placebo Ivabradine HR = 0.91 (0.80–1.03) P = 0.128 Swedberg K, et al. Lancet. 2010;online August 29. MonthsMonths Cumulative frequency (%)Cumulative frequency (%) 90 % of pts on BB and annual event rate in placebo is low (13%) ??
  126. 126. Baseline heart rate is a predictor of endpoints on placebo Primary composite endpoint: risk increases by 2.9% per 1-bpm increase, and by 15.6% per 5-bpm increase 50 40 30 20 10 0 0 6 12 18 24 30 Months ≥87 bpm 80 to <87 bpm 75 to <80 bpm 72 to <75 bpm 70 to <72 bpm P<0.001 Patients with primary composite endpoint (%) Böhm et al, Lancet 2010; 376: 886-894. Prospective Study
  127. 127. Baseline heart rate is a predictor of endpoints on placebo 50 40 30 20 10 0 0 6 12 18 24 30 Months ≥87 bpm 80 to <87 bpm 75 to <80 bpm 72 to <75 bpm 70 to <72 bpm P<0.001 Hospital admission for heart failure (%) ≥87 bpm 80 to <87 bpm 75 to <80 bpm 72 to <75 bpm 70 to <72 bpm 50 40 30 20 10 0 0 6 12 18 24 30 Months Cardiovascular death (%) P<0.001 Böhm et al, Lancet 2010; 376: 886-894.
  128. 128. Benefit of ivabradine in all prespecified subgroups
  129. 129. Patients with an adverse event, leading to withdrawal Ivabradine N=3232, n (%) Placebo N=3260, n (%) p value All adverse events 467 (14%) 416 (13%) 0.051 Symptomatic bradycardia 20 (1%) 5 (<1%) 0.002 Asymptomatic Bradycardia 28 (1%) 5 (<1%) <0.0001 Atrial fibrillation 135 (4%) 113 (3%) 0.137 Phosphenes 7 (<1%) 3 (<1%) 0.224 Blurred vision 1 (<1%) 1 (<1%) 1.000 Treatment discontinuation Swedberg K, et al. Lancet. 2010; online August 29.
  130. 130. Inger ekman et al. European Heart Journal: August 29 2011 Ivabradine improves HQoL in HF patients Sub-group analysis from SHIFT Assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ) 1944 patients (968 ivabradine, 976 placebo)
  131. 131. Ivabradine increases LVEF European Heart Journal doi:10.1093/eurheartj/ehr311 ACEI+BB+MR antagonist + Ivabradine n=204 ACEI+BB+MR antagonist n=199 Sub-group analysis from SHIFT 411 patients (ivabradine 208, placebo 203), assessed at baseline & 8 months
  132. 132. Conclusion •HF withwith systolic dysfunctionsystolic dysfunction and elevated HR is associated with poor outcomes (PCE in the placebo group is 18%/year) •Ivabradine reduced CV mortality or HF hospitalization by -18% •Mainly driven by effect on HF death & hospitalization by - 26% •Ivabradine was safe and well tolerated
  133. 133. Morbidity benefit of Ivabradine in Heart Failure compared to beta blockers CARVIVA HF
  134. 134. CARVIVA HF: prospective, randomised, open study N=123 pts, compare effects on exercise capacity and QoL with carvedilol, ivabradine, or combination Ivabradine, up to 7.5 mg bid N=42 Carvedilol, up to 25 mg bid N=39 Carvediolol/ivabradine, up to 12.5/5 mg bid N=42 Screening Baseline Randomisation End of study -8 -1 0 12Time (weeks)2 End of uptitration -5 optimize ACEI, washout any β-blocker Volterrani et al. Int. J. Cardiol. 2011;151:218-224 3 months 3 months
  135. 135. CARVIVA primary endpoint: Change in exerciseCARVIVA primary endpoint: Change in exercise capacitycapacity %changecomparedtobaseline *P<0.01 vs baseline. † P<0.01, †† P<0.02 vs carvediolol *† *†† *†† *† Volterrani et al. Int. J. Cardiol. 2011;151:218-224
  136. 136. Bagriy AE, Shchukina EV, Malovichko SI, Prikolota AV. Addition of Ivabradine to Carvedilol Reduces Duration of Carvedilol Uptitration and Improves Exercise Capacity in Patients with Chronic Heart Failure. J Am Coll Cardiol. 2013;61(10_S). doi:10.1016/S0735-1097(13)60700-7. Ivabradine increases exercise capacity • 41 patients in sinus rhythm with previous MI • CHF (NYHA class II-III), and HR ≥70 bpm. Carvedilol up to 25 mg bid + Ivabradine 7.5 mg BD Carvedilol up to 25 mg bid
  137. 137. Morbidity benefit of Ivabradine in Heart Failure on top of optimal treatment The INTENSIFY study: practical dailyThe INTENSIFY study: practical daily effectiveness and tolerance of ivabradine ineffectiveness and tolerance of ivabradine in chronic systolic heart failure in Germanychronic systolic heart failure in Germany Zugck C, Martinka P, Stöckl G. Ivabradine treatment in a chronic heart failure patient cohort: symptom reduction and improvement in quality of life in clinical practice. Adv Ther. 2014;31:961-974.
  138. 138. RESULTSRESULTS Ivabradine rapidly improves symptoms Zugck C, Martinka P, Stöckl G. Ivabradine treatment in a chronic heart failure patient cohort: symptom reduction and improvement in quality of life in clinical practice. Adv Ther. 2014;31:961-974.
  139. 139. +Ivabradine +Ivabradine Ivabradine reduces heart failure symptoms Zugck C et al. Ivabradine treatment is effective in chronic systolic heart failure in clinical practice irrespective of left ventricular ejection fraction at baseline. ClinRes Cardiol. 2014;103(Suppl 1):P1456.
  140. 140. IMPACT ON CLINICAL PRACTICEIMPACT ON CLINICAL PRACTICE The INTENSIFY study has shown that there is room for further symptomatic improvement in chronic heart failure patients, despite current treatments such as beta-blockers. Ivabradine has proven in clinical practice to be rapidly effective in reducing symptoms of heart failure, and improving quality of life in chronic heart failure patients. Zugck C, Martinka P, Stöckl G. Ivabradine treatment in a chronic heart failure patient cohort: symptom reduction and improvement in quality of life in clinical practice. Adv Ther. 2014;31:961-974.
  141. 141. Deschaseaux C et al. Efficacy of heart failure pharmacological treatment classes and combinations: network meta-analyses. Eur J Heart Fail. Abstracts Supplement. 2014;16(Suppl 2):161. Efficacy of heart failure pharmacological treatment classes and combinations: Network meta-analysis All-cause mortality rate per 100 person-years
  142. 142. Effect of Ivabradine on Morbi-mortality in CAD with normal LV function Evidences of Ivabradine
  143. 143. Ivabradine Starting dose 7.5 mg bid Placebo bid Run in 2 - 4 weeks M006M003M000 Every 6 months Target HR: 55-60 bpm Methods Events: 4.5% per year in the placebo group 1070 primary composite endpoints (cardiovascular death and non fatal MI N = 11 330, mean follow up = 2.5 years; RRR = 18%, α bilateral 5%, power 90% Population Outpatients with stable CAD without LVSD (EF > 40%) or clinical signs of HF, with appropriate CV medication
  144. 144. 95% CI [-10.0; -9.5] 9.7 bpm
  145. 145. Considerations First: the dosage • Higher dosages : Starting at 7.5 mg BD and uptitrated to 10 mg BD if heart rate >60 bpm • 51% patients received 10 mg BD 27% patients 7.5 mg BD and 22% patients 5 mg BD • Incidence of bradycardia in SIGNIFY was 17.9% Vs. 4.6% in BEAUTIFUL
  146. 146. • In SIGNIFY, 1135 patients received verapamil or diltiazem and 262 received stronger inhibitors of CYP 3A4 • Those receiving verapamil, diltiazem or strong CYP 3A4 inhibitors on top of Ivabradine had a 61% increase in primary end point and 93% increase in nonfatal MI • After excluding these patients, the risk versus placebo decreased Considerations 2: Concomitant use of diltiazem, verapamil or CYP 3A4 inhibitors
  147. 147. Considerations 2: Concomitant use of diltiazem, verapamil or CYP 3A4 inhibitors • Ivabradine is metabolized via CYP 3A4 • Diltiazem and Verapamil mildly inhibit CYP 3A4 and increase exposure to ivabradine, in addition to lowering heart rate • Ketoconazole or macrolide antibiotics are stronger inhibitors of CYP 3A4, and increase exposure to Ivabradine 7-8 fold
  148. 148. Morbi-mortality benefit of heart rate lowering depends on LV function
  149. 149. Conclusion of •It shows that HR reduction in CAD without HF is advantageous for symptoms relief, but does not improve outcomes. • Ivabradine should not be used in combination with Verapamil, Diltiazem, or ketoconazole, or macrolide antibiotics. • Ivabradine should be used at the usual dose of 5 mg BD uptitrated to 7.5 mg BD in order to avoid excessive bradycardia.
  150. 150. Case example in CCU MGH •60 yr male, ex-smoker, hypertension, stable angina since 2015.on ASA, Clopidogrel, Meroprolol, Nicorandil, Atorvastatin, Perindopril 12.8.2015
  151. 151. Oct 2015-Angina not improved- advised for revascularization- declined
  152. 152. 5 pm,8.5 2016- Severe angina, BP-80/60 admitted to CCU MGH Omit BB, ACEI IV Doubtamine
  153. 153. 8 am, 9.5 2016- Still angina, BP-110/70, orthopnoeic, pul oedema IV Doubtamine IV GTN IV Lasix
  154. 154. 11.5 2016- free of angina, BP-120/70, can lie in flat Added Ivabradine 5mg BD Uptitrated to 7.5mg BD next day
  155. 155. 14.5 2016- free of angina, BP-120/70, oral Lasix, awaiting for angio
  156. 156. CONCLUSION • High resting heart rate is a predictor of mortality in a large variety of populations: • General population • Prehypertensive patients • Hypertensive patients • Stable CAD patients • ACS patients • Post-MI patients • Heart failure patients
  157. 157. Ivabradine preserves global cardiac function Myocardial contractility Preserved1 Preserved2 Ventricular repolarization time Preserved2 1. Vilaine JP, Bidouard JP, Lesage BS, et al. J Cardiovasc Pharmacol. 2003;32:688-696. 2. Camm A, Lau CP. Drugs R&D. 2003;4:83-89. AV conduction time Blood Pressure Preserved2  
  158. 158. Pharmacological therapy for CHF patients 1. Diuretics 2. ACEI/ARB 3. Beta-blocker 4. Heart rate lowering - Digoxin - Ivabradine
  159. 159. Evidences of Ivabradine across Cardiovascular Continuum Remodeli ng Ventricular Dilation Chronic Heart Failure Myocardial Ischemia (angina) Atherosclerosis LVH Coronary Artery Disease Coronary Thrombosis Arrhythmi as End-Stage Heart Disease, Death Dyslipidemia Hypertensio n Diabetes Smoking Obesity Myocardial Infarction The Cardiovascular Continuum Dzau V et al. Circulation. 2006;114:2850-2870 INITIATIVEINITIATIVEINITIATIVEINITIATIVE Stable CAD & Normal EF CARVIVA HF
  160. 160. Ivabradine indicated for CAD patients Symptomatic treatment of chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm: •in patients with HR > 70 bpm - In addition to beta-blockers - As an alternative to beta-blockers Indication approved by the European Medicines Agency, 02/2012
  161. 161. Ivabradine indicated for chronic heart failure • Ivabradine is indicated in chronic heart failure NYHA II to IV class with systolic dysfunction, in patients in sinus rhythm and whose heart rate is ≥ 70 bpm • In combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated Indication approved by the European Medicines Agency, 02/2012
  162. 162. Typical Case • 55 yo man, smoker , history of CAD previous PCI, Ischemic cardiomyopathy, EF 35%, Severe COPD with frequent use of inhalers, comes to your clinic for follow-up, describing low grade stable angina for months (since PCI). • On carvedilol 6.25mg bid, perindropril 5mg, ASA, plavix, statin, ISMN 50mg • BP 110/60, HR 88 at rest. • What can we offer him? Ivabradine

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