role of ivabradine

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. 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. 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. 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. Heart rate : the first rhythm in our life

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. 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. 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. The higher Heart rate; The shorter life
span

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. I. High resting heart rate is an independent risk
factor for mortality in General population &
Hypertensive patients

13. 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

14. 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)

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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

16. 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

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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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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.

26. 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

28. Spectrum of CHD
•Silent ischaemia
•Stable Angina
•Acute Coronary Syndrome (UAP,NSTEMI,STEMI)
•Sudden Cardiac Death
•Ischaemic Cardiomyopathy
•Chronic Heart Failure

29. 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

30. II. Role of heart rate
in development of atherosclerosis

31. 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

32. 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

33. 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

34. III. Role of heart rate in
stable coronary artery disease
Heart rate & ischaemia

35. 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

36. HR <62 bpm
HR >78 bpm

37. 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

38. Increased heart rate worsens
ischaemia
Increased workload
Increased O2
demand
Decreased O2
supply
IschIschaaemiaemia
Decreased diastolic time
Increased heart rate

39. 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

40. 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

41. 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

42. Increased heart rate worsens
ischaemia
Increased workload
Increased O2
demand
Decreased O2
supply
IschIschaaemiaemia
Decreased diastolic time
Increased heart rate

43. Lowering heart rate relieves
ischaemia
Decreased workload
Decreased O2
demand
Preserved O2
supply
IschIschaaemiaemia
Increased diastolic time
Decreased heart rate

44. 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

45. 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.

46. A Diaz et al. EHJ 2005; 26: 976-74

47. IV. Role of heart rate in
acute coronary syndrome

48. 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

49. High Heart Rates are Predictive of Coronary
Plaque Ruptures
Heidland UE, Strauer BE. Circulation. 2001;104:1477-1482. AS-ct11-0706

50. 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

51. 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

52. V. Role of heart rate in
Postmyocardial infarction

53. 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.

54. 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.

55. 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

56. 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

57. 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

58. VI. High resting heart rate
in chronic heart failure

59. 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)

60. High resting heart rate is an independent
predictor of death in patients with heart failure
Lechat P. CIBIS II. Circulation. 2001:103:1428-1433.

61. 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

62. 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

66. American College of Cardiology /
American Heart Association
ACC/AHA guidelines. 2002.

67. Lowering heart rate
???new treatment option
A key objective to save lives
in both CAD & heart failure

68. With WHAT & HOW
we should lower it?

69. 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

70. 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

71. Effects of beta-blockers
= Reduces heart rate
= Reduces LV contraction
= Reduces conduction
= Reduces blood pressure
= Prevents coronary vasodilatation during exercise

72. 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

73. Are there anything more than
beta-blockers?

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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:

75.  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

76. 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

77. 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

78. -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!

79. Anti-ischemic efficacy of Ivabradine
compared to beta blockers
INITIATIVE

80. 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

81. 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

82. 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

83. 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

84. 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

85. 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

86. 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

87. 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

88. 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).

89. 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%

90. 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)

91. 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

92. -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 (%)

93. Does It Work in Clinical Practice?Does It Work in Clinical Practice?
ADDITIONSADDITIONS STUDYSTUDY

94. • 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.

95. 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

96. Effect of Ivabradine on
Morbi-mortality in CAD
Angina
Evidences of Ivabradine

97. 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

98. 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

99. 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

100. 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

101. 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

102. 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

103. 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

104. 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

105. Effect of ivabradine on the primary
endpoint (overall population)
Effect of ivabradine on the primary
composite endpoint (HR ≥ 70 bpm)

106. Effect of ivabradine in patients with HR ≥70 bpm
coronary revascularization
hospitalization for MI

107. 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%

108. 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.

109. 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.

110. 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

111. 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

112. 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

113. 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

114. 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

115. 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

116. 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

117.  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

118.  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

119. Effect of Ivabradine on
Morbi-mortality in AMI
Evidences of Ivabradine

121. Systolic Heart failure treatment with
the If inhibitor ivabradine Trial
Systolic Heart failure treatment with
the If inhibitor ivabradine Trial

122. 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

123. 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

124.  ≥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.

125. 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.

126. 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.

127. 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

128. 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

129. 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 (%)

130. 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 (%)

131. 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%) ??

132. 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

133. 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.

134. Benefit of ivabradine in all
prespecified subgroups

135. 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.

136. 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)

137. 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

138. 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

139. Morbidity benefit of Ivabradine in Heart Failure
compared to beta blockers
CARVIVA HF

140. 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

141. 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

143. 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

144. 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.

145. 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.

146. +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.

147. 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.

148. 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

149. Effect of Ivabradine on Morbi-mortality
in CAD with normal LV function
Evidences of Ivabradine

150. 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

154. 95% CI [-10.0; -9.5]
9.7 bpm

160. 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

161. • 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

162. 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

163. Morbi-mortality benefit of
heart rate lowering depends on LV function

164. 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.

165. 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

166. Oct 2015-Angina not improved- advised for
revascularization- declined

167. 5 pm,8.5 2016- Severe angina, BP-80/60
admitted to CCU MGH
Omit BB, ACEI
IV Doubtamine

168. 8 am, 9.5 2016- Still angina, BP-110/70,
orthopnoeic, pul oedema
IV Doubtamine
IV GTN
IV Lasix

169. 11.5 2016- free of angina, BP-120/70, can lie in
flat
Added Ivabradine 5mg BD
Uptitrated to 7.5mg BD next day

170. 14.5 2016- free of angina, BP-120/70, oral Lasix,
awaiting for angio

171. 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

172. 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



173. Pharmacological therapy for CHF patients
1. Diuretics
2. ACEI/ARB
3. Beta-blocker
4. Heart rate lowering
- Digoxin
- Ivabradine

175. 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

176. 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

177. 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

178. 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