& π 3 billion heart beats/lifetime

Transcript

1 π... 9

2 π π π π π π π

3 & π 3 billion heart beats/lifetime Levine H. J Am Coll Cardiol 1997;30:1104 6

4 & π Ηλικία (έτη) Εξέλιξη του προσδόκιµου επιβίωσης Ο άνθρωπος ξεχώρισε:0 Επιστήμη0 Ιατρική Έτος Birngruber,

5 Pathophysiological mechanisms promoted by increased heart rate Myocardial ischemia HR Ventricular function and remodelling Atherosclerosis

6 Pathophysiological mechanisms promoted by increased heart rate myocardial O 2 requirement Imbalance of O 2 supply/demand Diastolic duration Coronary perfusion time Myocardial ischemia HR Ventricular function and remodelling Atherosclerosis

7 Pathophysiological mechanisms promoted by increased heart rate Myocardial ischemia HR Ventricular function and remodelling Atherosclerosis Endothelial dysfunction Hemodynamic stress Plaque rupture Pulsatile shear stress

8 Pathophysiological mechanisms promoted by increased heart rate Myocardial ischemia Cardiac Noradrenaline synthesis HR Ventricular function and remodelling Atherosclerosis apoptosis

9 Pharmacological approaches for reducing heart rate Cardiac site of action Effect in cardiac system HR reduction β-blockers Sinus node A-V node ventricule HR reduction (-) Dromotropic effect (-) Inotropic effect - 15,6 bpm 1 Non dihydropyridine calcium antagonist (verapamil, diltiazem) Sinus node A-V node ventricule HR reduction (-) Dromotropic effect (-) Inotropic effect - 7,0 bpm 2 I f Inhibitors : ivabradine Sinus node HR reduction - 14,3 bpm 1 1. Tardif JC, et al. Eur Heart J. 2005;26: Vliegen HW, et al. J Cardiovasc Pharmacol. 1991;18(suppl.19):S55-S60.

10 : & & Seccareccia F, et al. Am J Public Health. 2001;91:1258. / The MATISS Project (bpm)

11 : & < > 75 (bpm) Jouven X, et al. N Enlg J Med. 2005;352:1951.

12 : π π π < > 80 (bpm) Benetos A,et al. Am J Geriatr Soc. 2003;51:284.

13 & π

14 π π : π The Framingham Study π < > 84 (bpm) Gillman, et al. Am Heart J. 1993;125:1148.

15 Δοµή ελαστίνης σε τµήµατα αορτής Τίγρη, 15 ετών (64 bpm) Ιαγουάρος, 15 ετών (130 bpm) 15 years old tiger 505 million cycles 15 years old jaguar 1025 million cycles Avolio A, et al. Hypertension. 1998;32:

16 Lantelme P, et al. Hypertension 2002;39:

17 Benetos A, et al. Circulation. 2002;105:

18 π : & π Cook St.,et al. Eur Heart J. 2006;27:

19 &

20 : & π Προσαρµοσµένες καµπύλες επιβίωσης για Συνολική θνητότητα Προσαρµοσµένες καµπύλες επιβίωσης για Καρδιαγγειακή θνητότητα Αθροιστική επιβίωση Καρδιακή Συχνότητα <62 bpm >83 bpm Αθροιστική επιβίωση Έτη από την ένταξη (y) Έτη από την ένταξη (y) Diaz A et al. Eur Heart J. 2005;26:

21 Annual event rates in stable CAD outpatients REACH registry (n=38.602) CHF CABG PCI UA Death/MI/Stroke/Hosp* Death/MI/Stroke Nonfatal Stroke Nonfatal MI CV Death 1,4 1,4 1,4 1,8 3,8 4,5 6,9 6,44 15, Rates adjusted for age and risk factors Steg PG et al. JAMA. 2007;297:

22 Κανονικ ή αρτηρία- Αρτηρία με στένωσ η- Nabel et al., Circulation 81:1990:850

23 Φυσιολογική Παθολογική Ροή 1 Παράπλευρα Πίεση 1 Πίεση 2 Ροή 2 LAD LCX -

24 2 Boudoulas H. Circulation 1979;60:

25 π O 2 π Καρδιακή Συχνότητα Μεταφορτίο Προφορτίο Τοιχ. Stress Συσταλτικότητα Opie LH: The Heart, Physiology, from Cell to Circulation. Philadelphia, Lippincott Raven, 1998

26 π O 2 π Αύξηση MVO2 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% Τοιχω ματικ ή Τάσ η MVO 2 π 50% : Συσ ταλτικότητα Έργο Πίεσ ης Καρδιακή Συχνότητα Gould KL: Coronary Artery Stenosis. New York, Elsevier, 1991

27 2 20 DOG 4 20 DOG 5 20 DOG 6 Κατανάλωση Ο 2 (ml/min/100g) DOG DOG DOG 6 Κατανάλωση Ο 2 (ml/beat/100g) Heart rate (min -1 ) Tanaka et al., Jap J Physiol 40: , 1990

28 2 MVO 2 (ml O 2 /min) Saline Ivabradine 0,5 mg/kg Ivabradine 1 mg/kg -10% * -19% * Rest Exercise *P<0.05 vs Saline Colin P. JPET 2004; 308:

29 Καρδιακή Συχνότητα 100 (bmp) ** ** ** ** * * * Στηθάγχη Κατάσπαση του ST Σύµβαµα Χρόνος (min) Kop W, et al. J Am Coll Cardiol. 2001;38:742.

30 π Ρήξη της Πλάκας Αθηροσκλήρυνση Ενδοθηλιακή Δυσλειτουργία Υπέρταση, Δυσλιπιδαιµία, Κάπνισµα, Διαβήτης Στεφανιαία Νόσος ΟΕΜ Δυσλειτουργία της ΑΚ Remodeling Καρδιακή Ανεπάρκεια Θάνατος

31 π π Καρδιακής Συχνότητας Χρόνου Διαστολικής πλήρωσης Μεταβολικών αναγκών Καρδιακής Συχνότητας Στεφανιαίας αιµατικής ροής Ανάγκες O 2 Προσφορά O 2 Kop W, et al. J Am Coll Cardiol. 2001;38:742

32 π Adverse outcome incidence (%) Outcome (all-cause death, non-fatal MI, or nonfatal stroke) 4.0 Hazard ratio Estimated hazard ratio Mean follow-up heart rate (bpm) INVEST study, CAD patients; 2,7-year follow-up Kolloch et al., Eur Heart J. 2008;29:

33 - π π π π

34 π > 70 bpm, Ivabradine -. > 70 bpm, Ivabradine Fox K et al. Lancet, 2008; 372:

35 π H Ivabradine π - π,.

36 & π

37 π : π CIBIS II, Circulation. 2001:103: (%) placebo bisoprolol 0 72 bpm 72< 84 bpm > 84 bpm

38 Thus, there is evidence both in animals and in human beings that an elevated heart rate is conducive to atherosclerosis and its clinical manifestations. Palatini P, Benetos A, Grassi G, Julius S, Kjeldsen SE, Mancia G, Narkiewicz K, Parati G,. Pessina AC, Ruilope LM and Zanchetti A: Identification and management of the hypertensive patient with elevated heart rate: statement of a European Society of Hypertension Consensus Meeting Journal of Hypertension 2006, 24:

39 ( ) π π π π π & π π π European Heart Journal 2006; 27:

40 π π π π π π π π π European Heart Journal 2006; 27:

41

42 : & π CASS Registry Προσαρµοσµένες καµπύλες επιβίωσης για Συνολική θνητότητα Προσαρµοσµένες καµπύλες επιβίωσης για Καρδιαγγειακή θνητότητα bpm Cumulative survival P< P< Έτη παρακολούθησης CAD patients; 14,1-year follow-up Diaz A et al. Eur Heart J. 2005;26:

43 The role of heart rate in the continuum of cardiovascular disease

44 Heart Rate & Survival Heart Rate (Beats /min) Mouse Hamster Rat Monkey Marmot Cat Dog Giraffe Tiger Ass Horse Elephant Lion Whale Whale Man Life Expectancy (Years) Levine et al. J Am Coll Cardiol. 1997;30:

45 Heart rate & Life Expectancy The progression of life expectancy Age (years) Human is different: Science Medicine Year Birngruber,

46 General Population: HR & Sudden Death 4 3 Total deaths ACI Sudden Death Relative Risk < > 75 HR (bpm) Jouven X, et al. N Engl J Med. 2005;352:1951.

47 Elderly: HR as a risk factor Adjusted relative risk survival elderly men < > 80 HR (bpm) Benetos A,et al. Am J Geriatr Soc. 2003;51:284.

48 Cardiovascular disease: Role of Heart Rate in the CV Continuum Myocardial Infarction & Stroke Remodeling Ventricular Dilation/ Cognitive Dysfunction Congestive Heart Failure/ Secondary Stroke Atherosclerosis and LVH Risk factors Diabetes Hypertension Heart Rate End-Stage Heart Disease/ Brain Damage & Dementia Cardio/ Cerebrovascular Death Adapted from Dzau V and Braunwald E. Am Heart J. 1991;121:

49 Cardiovascular disease: Role of Heart Rate in the CV Continuum Hypertension Myocardial Infarction & Stroke Remodeling Ventricular Dilation/ Cognitive Dysfunction Congestive Heart Failure/ Secondary Stroke Atherosclerosis and LVH Risk factors Diabetes Hypertension Heart Rate End-Stage Heart Disease/ Brain Damage & Dementia Cardio/ Cerebrovascular Death Adapted from Dzau V and Braunwald E. Am Heart J. 1991;121:

50 Hypertensive Population: HR as a risk factor Age-Adjusted 2-Year Mortality Rate per Coronary Heart Disease Cardiovascular Disease All cause The Framingham Study < > 84 ΚΣ (bpm) Gillman, et al. Am Heart J. 1993;125:1148.

51 Increase of aortic stiffness & Heart rate Tiger, 15 years-old (64 bpm) The structure of elastin in aortic parts Jaguar, 15 years-old (130 bpm) Avolio A, et al. Hypertension. 1998;32:

52 Increase of aortic stiffness & Heart rate Clinical data Lantelme P, et al. Hypertension 2002;39:

53 Increase of aortic stiffness & Heart rate Clinical data Benetos A, et al. Circulation. 2002;105:

54 Thus, there is evidence both in animals and in human beings that an elevated heart rate is conducive to atherosclerosis and its clinical manifestations. Palatini P, Benetos A, Grassi G, Julius S, Kjeldsen SE, Mancia G, Narkiewicz K, Parati G,. Pessina AC, Ruilope LM and Zanchetti A: Identification and management of the hypertensive patient with elevated heart rate: statement of a European Society of Hypertension Consensus Meeting Journal of Hypertension 2006, 24:

55 Cardiovascular disease: Role of Heart Rate in the CV Atherosclerosis Plaque rupture Continuum Hypertension Myocardial Infarction & Stroke Remodeling Ventricular Dilation/ Cognitive Dysfunction Congestive Heart Failure/ Secondary Stroke Atherosclerosis and LVH Risk factors Diabetes Hypertension Heart Rate End-Stage Heart Disease/ Brain Damage & Dementia Cardio/ Cerebrovascular Death Adapted from Dzau V and Braunwald E. Am Heart J. 1991;121:

56 Preclinical Data

57 HR reduction and atherosclerosis progression Monkeys; high-cholesterol diet for 6 months Maximum stenosis (%) P<0.02 Sinus node ablation 0 High Low Heart rate Beere PA, et al. Science. 1984;226:

58 Heart Rate in WT, ApoE KO and Treatment Groups 700 ** Heart rate (bpm) ** ** 400 Vehicle Iva 10 Iva 2 Iva 10 + L-NAME Hydra Custodis et al. Circulation. 2008;117(18):

59 Aortic Atherosclerosis in WT, ApoE KO and Treatment Groups 40 Plaque Area (% total) * 0 Aortic Sinus 30 Plaque Area (% total) * Vehicle Ivabradine Vehicle Ivabradine 0 Ascending Aorta Custodis et al. Circulation. 2008;117(18):

60 Clinical Data

61 HR reduction and reduction of Ischemia 63 stable angina patients and frequency if asymptomatic ischeamia Larger heart rate reduction is associated with bigger reduction in ischaemic episodes Stone PH. Circulation. 1990;82:

62 Coronary Artery Disease: HR & Survival CASS Registry Adjusted survival curves for Overall mortality Adjusted survival curves for CV mortality bpm Cumulative survival P< P< Years of follow-up CAD patients; 14,1-year follow-up Diaz A et al. Eur Heart J. 2005;26:

63 The prognostic value of HR in patients with hypertension and Coronary Artery Disease Adverse outcome incidence (%) Outcome (all-cause death, non-fatal MI, or nonfatal stroke) Hazard ratio Estimated hazard ratio Mean follow-up heart rate (bpm) INVEST study, CAD patients; 2,7-year follow-up Kolloch et al., Eur Heart J. 2008;29:

64 Heart Rate and Coronary Plaque Rupture Heidland UE, Strauer BE. Circulation. 2001;104:

65 Possible mechanisms through which high Heart Rate provokes atherosclerosis Increases mechanical work in arterial wall Provokes structural and functional changes in endothelial cells Weakens the fibrotic π, leading to plaque rupture and the occurrence of acute coronary syndromes

66 Cardiovascular disease: Role of Heart Rate in the CV Atherosclerosis Plaque rupture Continuum Post MI Hypertension Myocardial Infarction & Stroke Remodeling Ventricular Dilation/ Cognitive Dysfunction Congestive Heart Failure/ Secondary Stroke Atherosclerosis and LVH Risk factors Diabetes Hypertension Heart Rate End-Stage Heart Disease/ Brain Damage & Dementia Cardio/ Cerebrovascular Death Adapted from Dzau V and Braunwald E. Am Heart J. 1991;121:

67 -blockers in post-myocardial Infraction (MI) patients 1 year post-mi mortality 6 months post-mi mortality Mortality (%) Göteborg-Metoprolol Trial < > HR (bpm) Mortality (%) ,9 < 60 [n=4.038] 3, [n=5.600] 9, [n=1.278] 20,2 > 100 [n=114] HR (bpm) Hjalmarson A, et al. Am J Cardiol. 1990;65: Tavazzi L. Eur Heart J. 2003;5:G15-G18.

68 HR reduction with -blockade & ACI mortality R=0.79 P<0.005 Kjekshus J. Eur Heart J 1985;6:A29, Am J Cardiol 1986;57:43F

69 Relative risk (log) HR reduction & Cardiac Death: Post- MI patients Meta-regression of 17 controlled trials in MI survivors patients treated with beta-blockers or calcium antagonists β-blockers Calcium channel blockers P< HR (bpm) The beneficial effect of beta-blockers and calcium channel blocke post-mi patients is proportionally related to resting HR reduction Cucherat M. Eur Heart J. 2007;28:

70 Cardiovascular disease: Role of Heart Rate in the CV Atherosclerosis Plaque rupture Continuum Post MI Remodeling and Heart Failure Hypertension Myocardial Infarction & Stroke Remodeling Ventricular Dilation/ Cognitive Dysfunction Congestive Heart Failure/ Secondary Stroke Atherosclerosis and LVH Risk factors Diabetes Hypertension Heart Rate End-Stage Heart Disease/ Brain Damage & Dementia Cardio/ Cerebrovascular Death Adapted from Dzau V and Braunwald E. Am Heart J. 1991;121:

71 Cleland J et al, Am Heart J 2006;152:713 HR & LV function in Heart Failure patients End-diastolic/ end-systolic Volumes Ejection Fraction 30 3 Changes in volumes (ml) LVEDV LVESV 60 bpm 80 bpm LVEDV LVESV change (%) bpm 80 bpm -70 b-blocker + PACING 80bpm b-blocker + PACING 60bpm -5 b-blocker + PACING 80bpm b-blocker + PACING 60bpm

72 Heart Failure: Heart Rate as a risk factor placebo bisoprolol 1 year mortality (%) HR 0 At inclusion 72 bpm 72< At inclusion 84 bpm At inclusion > 84 bpm CIBIS II, Circulation. 2001:103:1428.

73 Heart Rate reduction and mortality reduction in HF patients XAMOTEROL PROFILE Change in mortality (%) 20 PROMISE VHeFT (prazosin) CIBIS NOR TIMOLOL MOCHA BHAT GESICA ANZ US CARVEDILOL SOLVD CONSENSUS VHeFT (HDZ/ISDN) Change in HR (bpm) Swedberg K et al. Eur Heart J. 1999;20:

74 High Heart Rate Prognostic factor in the general population and in patients with CAD The existing evidence comes from observational studies (retrospective data) This hypothesis wasn t proven perspectively

75 Heart Rate reduction Heart Rate reduction in patients with stable Coronary Artery Disease could improve clinical outcomes This hypothesis hasn t been proven perspectively

76 Unique opportunity to prospectively study: Heart rate as a predictor of outcome in CAD Effect of pure heart reduction on outcome in CAD patients

77 Fox K et al. Lancet Online August 31, 2008.

78 Objective To examine the effects of high heart rate on the prevention of cardiovascular events in patients with coronary artery disease and left ventricular systolic dysfunction

79 End-points Primary (combined) : Cardiovascular death. Admission for AMI. Admission for acute heart failure. Secondary end-points: The composite of hospitalization for ACS, for newonset or worsening heart failure, or coronary revascularization All-cause mortality. Mortality due to coronary artery disease. Fatal or non-fatal AMI. The individual components of the composite primary and secondary end points. Fox K et al. Lancet Online August 31, 2008.

80 Study population 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) Fox K et al. Lancet Online August 31, 2008.

81 Baseline characteristics at inclusion (placebo group ) HR<70 HR 70 Number of patients Age, years Men, % Systolic BP, mm Hg Diastolic BP, mm Hg Heart Rate (at rest), bpm Ejection Fraction, % Values in parentheses are standard deviations Fox K et al. Lancet Online August 31, 2008.

82 Baseline characteristics HR<70 HR 70 at inclusion NYHA class I, % II, % III, % Ejection Fraction, % 32,7 31,9 Fox K et al. Lancet Online August 31, 2008.

83 Medical history HR<70 HR 70 Previous MI, % Previous PCI /CABG, % History of diabetes, % History of Hypertension, % Values in parentheses are standard deviations Fox K et al. Lancet Online August 31, 2008.

84 Concomitant treatment HR<70 HR 70 Antithrombotic agents, % Statines, % β-blockers, % Renin-angiotensin system agents, % Fox K et al. Lancet Online August 31, 2008.

85 Results Fox K et al. Lancet Online August 31, 2008.

86 Heart Rate as prognostic factor in the placebo group Primary compined end-point % of patients with primary end-point 25 P < Heart rate 70 bpm Heart rate < 70 bpm Years Fox K et al. Lancet Online August 31, 2008.

87 Heart Rate as prognostic factor in the placebo group Cardiovascular Death % with cardiovascular death 15 Hazard ratio = 1.34 ( ) P = Heart rate 70 bpm % 5 Heart rate < 70 bpm Έτη Fox K et al. Lancet Online August 31, 2008.

88 Heart Rate as prognostic factor in the placebo group % Admission to hospital for Heart Failure 15 Admission to hospital for Heart Failure Hazard ratio = 1.53 ( ) P < Heart rate 70 bpm % 5 Heart rate < 70 bpm Years Fox K et al. Lancet Online August 31, 2008.

89 Heart Rate as prognostic factor in the placebo group % admission to hospital for fatal or non fatal myocardial infarction 10 Myocardial Infarction 5 +46% Heart Rate 70 bpm Heart Rate < 70 bpm Years P=0.006 Fox K et al. Lancet Online August 31, 2008.

90 Heart Rate as prognostic factor in the placebo group % with event of coronary revascularisation 6 Hazard ratio = 1.38 ( ) P = Coronary revascularisation Heart rate 70 bpm 4 +38% 2 Heart rate < 70 bpm Years Fox K et al. Lancet Online August 31, 2008.

91 Conclusion High Heart Rate is a risk factor of cardiovascular morbidity & mortality, independent of other major risks factors HR measurement should: be used for the evaluation of cardiovascular risk guide optimal medical treatment in coronary patients Fox K et al. Lancet Online August 31, 2008.

92 π... 9

93 & π Mouse Hamster Heart Rate (Beats /min) Rat Marmot Dog Tiger Monkey Cat Ass Giraffe Elephant Whale Horse Lion Whale Man Life Expectancy (Years) Levine et al. J Am Coll Cardiol. 1997;30:

94 : & Σχετικός κίνδυνος Σύνολο Θανάτων ΟΕΜ Αιφνίδιος Θάνατος 0 < > 75 ΚΣ (bpm) Jouven X, et al. N Engl J Med. 2005;352:1951.

95 : & π CASS Registry Προσαρµοσµένες καµπύλες επιβίωσης για Συνολική θνητότητα Προσαρµοσµένες καµπύλες επιβίωσης για Καρδιαγγειακή θνητότητα bpm Cumulative survival P< P< Έτη παρακολούθησης CAD patients; 14,1-year follow-up Diaz A et al. Eur Heart J. 2005;26:

96 MorBidity-mortality EvAlUation of The I f inhibitor ivabradine in patients with coronary disease and left ventricular dysfunction Fox K et al. Lancet Online August 31, 2008.

97 π π π π.

98 Annual event rates in stable CAD outpatients REACH registry (n=38.602) CHF CABG PCI UA Death/MI/Stroke/Hosp* Death/MI/Stroke Nonfatal Stroke Nonfatal MI CV Death 1,4 1,4 1,4 1,8 3,8 4,5 6,9 6,44 15, Rates adjusted for age and risk factors Steg PG et al. JAMA. 2007;297:

99 π.

100 π π π. π π, - π

101 Gi π Ca π T - AC + camp Gs π β- π f P P Ca π L K

102 π Ca 2+ mv 0-50 Na + K ms pa I f I K I Ca,L I Ca,T I Na,Ca Προσαρµογή από DiFrancesco D, Camm AJ. Drugs. 2004;64:

103 I f -f 0 mv -40 mv -70 mv I f Το ρεύµα I f καθορίζει την κλίση της διαστολικής εκπόλωσης, τη συχνότητα των δυναµικών ενέργειας και, συνεπώς, την καρδιακή συχνότητα Προσαρµογή από DiFrancesco D, Camm AJ. Drugs. 2004;64:

104 f Ivabradine Προσαρµογή από DiFrancesco D, Camm AJ. Drugs. 2004;64:

105 I f 0 mv -40 mv -70 mv RR PROCORALAN Ivabradine π Η αναστολή του ρεύµατος Ι f οδηγεί σε µείωση της κλίσης διαστολικής εκπόλωσης στα κύτταρα του φλεβόκοµβου Προσαρµογή από Thollon C et al. Br J Pharmacol 1994; 112:37-42.

106 I f 0 mv -40 mv -70 mv RR Ivabradine π Η αναστολή του ρεύµατος Ι f οδηγεί σε µείωση της κλίσης διαστολικής εκπόλωσης στα κύτταρα του φλεβόκοµβου Thollon C et al. Br J Pharmacol 1994; 112:37-42.

107 π π π π.

108 The CASS registry: n= (%) π (%) P<

109 The CASS registry: n= Κλάσµα Εξώθησης (%) Επιβίωση (%) P< Έτη Emond M. Circulation. 1994;90:

110 π ( 70 / π ) π

111 781 π Northern Europe Austria Belgium Denmark Finland France Germany Ireland Netherlands Norway Sweden Switzerland UK North America Canada Latin America Argentina Brazil Southern Europe Greece Italy Portugal Spain Eastern Europe Czech Republic Hungary Poland Romania Russia Slovakia Australia Oriental Europe Bulgaria Estonia Latvia China Lithuania Slovenia Ukraine Near & Middle East Turkey Kim Fox, Roberto Ferrari, Michael Tendera et al. Am Heart J 2006;152:860-6.

112 Ivabradine: 5mg bid 2, 7,5mg Run-in Ivabradine 7.5 mg bid n=5479 π ( -2) Placebo M 0 M 12 M 18 M 24 M 30 M 36, M 6 n=5438 Event rate: 6-8%/ RRR: 20% Kim Fox, Roberto Ferrari, Michael Tendera et al. Am Heart J 2006;152:860-6.

113 Placebo Ivabradine n=5.438 n=5.479 n= NYHA class I, % II, % III, % %, , 32 % Fox K et al. Lancet, 2008; 372:

114 Placebo Ivabradine, 94 % 94, % π, % 87 87, % Fox K et al. Lancet, 2008; 372:

115 Placebo Ivabradine, 94 % 94, % π, % 87 87, % Fox K et al. Lancet, 2008; 372:

116 π P < π π placebo 70 bpm < 70 bpm Fox K et al. Lancet, 2008; 372:

117 % π P < π π placebo π Hazard ratio = 1.53 ( ) +53% 70 bpm < 70 bpm Fox K et al. Lancet, 2008; 372:

118 % µε θάνατο P = 0,0041 π π placebo +34% 70 bpm < 70 bpm Fox K et al. Lancet, 2008; 372:

119 P= π π placebo +46% 70 bpm < 70 bpm Fox K et al. Lancet, 2008; 372:

120 % π P = 0,037 π π placebo π +38% 70 bpm < 70 bpm Fox K et al. Lancet, 2008; 372:

121 π Ivabradine π ( π, n=10.917) = 1,00 (0,91 1,10) P = 0,94 Ivabradine Placebo Fox K et al. Lancet, 2008; 372:

122 (bp π (n=10.917) Ivabradine: 6,18 mg (2 / ) Placebo Ivabradine ( ) Fox K et al. Lancet, 2008; 372:

123 (bp ( 70 / π, n=5.392) Ivabradine: 6,64 mg (2 / Placebo ( ) Fox K, et al. Lancet. In press. Fox K et al. Lancet, 2008; 372: Ivabradine

124 π Ivabradine π ( 70 / π, n=5.392) % 8 P = 0,001-36% Placebo 4 Ivabradine Fox K et al. Lancet, 2008; 372:

125 π Ivabradine π ( 70 / π, π n=5.392) 8 P = 0,016 Placebo 4-30% Ivabradine PCI: 1,29 vs 1, / CABG: 0,47 vs 0, / Fox K et al. Lancet, 2008; 372:

126 π Ivabradine ( 70 / π, n=5.392) P 0,68 32% 0,114 0,64 0,78 36% & 22% 0,001 0,023 0,77 23%, π 0,009 π 0,70 30% 0,016 Fox K et al. Lancet, 2008; 372:

127 Ivabradine: H π ( BEAUTIFUL), π π π 70 bpm. -.

128 - π, 50% > 70 bpm % 70 bpm 53% Euro Heart Survey 40% 20 0 π π ( - π ) - π Euro Heart Survey in stable angina ESC 08

129 - π Inconsistent Users 18% Use to No Use 5% Always Users 37% Never Users 30% Ασθενείς µε ΣΝ ( ) Positive Converters 10% Califf R et al Circulation 2006;113: