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Heart rate: A global target for cardiovascular disease and therapy along the
cardiovascular disease continuum
Prof Kyaw Soe WinMBBS, 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
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
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
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
Heart rate : the first rhythm in our life
per day: 80 x 60 min x 24 h = 115.200 beats per year: 42.048.000 beats80 years: 3.363.840.000 beats
~300 mg ATP per beat~ 30 kg ATP per day
Heart Rate Reduction by 10 beatssaves ~ 5 kg ATP per day
Heart Rate – marker of metabolism
Ferrari et al. EHJ 2008, 10(Suppl) F7-10.
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!
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.
The higher Heart rate; The shorter life span
I. High resting heart rate and mortality in General population & Hypertensive patients
II. Role of heart rate in development of atherosclerosisIII. Role of heart rate in stable coronary artery diseaseIV. Role of heart rate in acute coronary syndromeV. Role of heart rate in postmyocardial infarctionVI. Role of heart rate in chronic heart failureVII. New treatment option by slowing heart rate with Ivabradine
Effect of Ivabradine on Morbi-mortality in CAD Effect of Ivabradine on Morbi-mortality in CHFAnti-ischemic efficacy of Ivabradine in patients already treated with beta blockers
Outlines
I. High resting heart rate is an independent risk
factor for mortality in General population &
Hypertensive patients
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
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 ‘80 Chicago Gas Company ‘80 1,233 M1,233 M 15 y15 y >94 vs. >94 vs. <<60 bpm 60 bpm 2.32.3Chicago Heart Ass.Project ’80Chicago Heart Ass.Project ’80 33,781 M&W 33,781 M&W 22 y22 y >>90 vs. <70 bpm 90 vs. <70 bpm M: 1.6 W: 1.1 (ns)M: 1.6 W: 1.1 (ns)Framingham ‘93 Framingham ‘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 bpm 90 bpm IHD death 3.3IHD death 3.3Spandau ’97Spandau ’97 4,756 M&W4,756 M&W 12 y12 y Sudden death Sudden death 5.2 per 20 bpm5.2 per 20 bpmBenetos ’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&W 1,938 M&W 12 y12 y 5th vs. 3rd quintile 5th vs. 3rd quintile M: 1.6 W: 1.1M: 1.6 W: 1.1Cordis ’00Cordis ’00 3,257 M3,257 M 8 y8 y >>90 vs. <70 bpm 90 vs. <70 bpm 2.02.0Reunanen ’00Reunanen ’00 10,717 M&W10,717 M&W 23 y 23 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 y 14 y >80 vs. >80 vs. <<80 bpm80 bpm <55y:1.5 >55y:1.3<55y:1.5 >55y:1.3Matiss ’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: 2.7Ohasama ‘04 Ohasama ‘04 1,780 M&W 1,780 M&W 10 y 10 y M: 1.2 W: 1.1 (ns) per 5 bpmM: 1.2 W: 1.1 (ns) per 5 bpmOkamura ‘04 Okamura ‘04 8,800 M&W 8,800 M&W 16.5 y 16.5 y per 11 bpm (1 SD) M: 1.3 W: 1.2per 11 bpm (1 SD) M: 1.3 W: 1.2Jouven ’05Jouven ’05 5 713 M5 713 M 23 y 23 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 RR Cardiovascular mortality RR
Epidemiological studies on the relationship Epidemiological studies on the relationship between HR and CV mortality between HR and CV mortality (general population (general population
and HTN)and HTN)
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Resting heart rate and all-cause mortality Resting 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
Rat
e/10
00 s
ubje
cts/
year
Men, 35-64 years Men, 65-94 years
Heart Rate (bpm)
30-67
68-75
76-83
84-91
92-220
1987
Mensink and Hoffmeister. Eur Heart J. 1997;18:1404-1410
Resting heart rate and all-cause mortality for Resting heart rate and all-cause mortality for 12 years in general population12 years in general population
0
5
10
15
20
25
Mor
talit
y %
<60 60-70 70-80 80-90 >90Heart 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 probability Resting heart rate and survival probability in in French general population (men)French general population (men)
1999
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
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
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
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 causeNon-sudden death from myocardial infarctionNon-sudden death from myocardial infarctionSudden death from myocardial infarctionSudden death from myocardial infarction
Resting heart rate and risk of mortality Resting heart rate and risk of mortality in general populationin general population
n=5713n=5713
2005
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
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
Rela
tive
risk
Resting heart rate (bpm)<60 60-64 65-69 70-75 >75
P<0.001
2.5 times
Resting heart rate and cardiovascular Resting heart rate and cardiovascular deaths in in the type 2 diabetic patients deaths in in the type 2 diabetic patients
0022446688
101012121414161618182020
46-69 bpm46-69 bpm 70-75 bpm70-75 bpm 76-89 bpm76-89 bpm >90 bpm>90 bpm
Car
diov
ascu
lar d
eath
, (n)
Car
diov
ascu
lar d
eath
, (n)
Linnemann B, Janka BU, Exp Clin Endocrinol Diabetes 2003;111:215-222
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.
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 t
o ≤ 55
> 55 t
o < 60
> 60 t
o ≤ 65
> 65 t
o ≤ 70
> 80 t
o ≤ 85
> 85 t
o ≤ 90
> 70 t
o ≤ 75
> 75 t
o ≤ 80
> 90 t
o ≤ 9
5
> 95 t
o ≤ 1
00
> 100
Adv
erse
out
com
e in
cide
nce
(%)
Estim
ated hazard ratio
Spectrum of CHD
•Silent ischaemia•Stable Angina•Acute Coronary Syndrome (UAP,NSTEMI,STEMI)•Sudden Cardiac Death•Ischaemic Cardiomyopathy•Chronic Heart Failure
Evidences across Cardiovascular Continuum
Remodeling
Ventricular Dilation
Chronic Heart Failure
Myocardial Ischemia (angina)
AtherosclerosisLVH
Coronary Artery Disease
Coronary Thrombosis Arrhythmi
as
End-StageHeart Disease,Death
DyslipidemiaHypertensionDiabetesSmokingObesity
Myocardial Infarction
The Cardiovascular
Continuum
Dzau V et al. Circulation. 2006;114:2850-2870
Stable CAD & Normal EF
II. Role of heart rate
in development of atherosclerosis
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)
Coronary arterial flow (myocardial perfusion)
Increased shear stressLow and oscillatory shear stress
Coronary arteries are prone to atherosclerosis
High heart rate acceleratescoronary atherosclerosis progression
Average coronary Average coronary stenosis (%)stenosis (%)
Atherosclerotic area (mmAtherosclerotic area (mm22))
Beere PA, et al. Science. 1984;226:180-182.
00
1010
2020
3030
4040
5050
6060P<0.02P<0.02 P<0.05P<0.05
High HRHigh HR Low HRLow HR00
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
Perski A, et al. Am Heart J. 1988;116:1369-1373.
Heart rate and coronary atherosclerosis
Minimum heart rate (bpm)
Cor
o nar
y a
ther
oscl
eros
is s
core
(%)
500
4
1
2
3
40 60 70 80 90
r= 0.70P<0.002
16 MI survivors, 6-month follow-up; 2 coronary angiographies; 24-hour ECG
III. Role of heart rate in
stable coronary artery disease
Heart rate & ischaemia
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
HR <62 bpm
HR >78 bpm
Elevated Heart RateElevated Heart Rate
IschemiaIschemia Major CV eventsMajor CV events
Increased OIncreased O22 demand demandDecreased supplyDecreased supply
Progression of Progression of atherosclerosisatherosclerosis
PlaquePlaquerupturerupture
Short term Long term
Atherosclerosis
Vascular damageVascular damage
Role of elevated HR in the pathophysiology of CAD
Increased heart rate worsens ischaemia
Increased workload
Increased O2 demand
Decreased O2 supply
IschIschaaemiaemia
Decreased diastolic time
Increased heart rate
Heart rate is associated with increased risk of major Heart 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 bpmQ5 Q5 >> 79 bpm 79 bpm
Q3 65-70 bpmQ3 65-70 bpmQ2 59-64 bpmQ2 59-64 bpmQ1 Q1 << 58 bpm 58 bpm
0
0.05
0.10
0.15
0.20
0.25
Years of follow-up0 1 2 3 4 5
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 80-89 70-79 80-89 >89>89
Heart rate at rest, bpmHeart rate at rest, bpm
XX 2 2 timestimes
Isch
emia
Heart Rate as a predictor of coronary events
Aronov W. S et al. Am J Cardiol. 1996;78:1175-1176
New coronary New coronary events, % events, %
<60<60 61-7061-70 71-8071-80 81-9081-90 91-10091-100 >100>10000
1010
2020
3030
4040
5050
6060
7070 XX 2 2 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
Increased heart rate worsens ischaemia
Increased workload
Increased O2 demand
Decreased O2 supply
IschIschaaemiaemia
Decreased diastolic time
Increased heart rate
Lowering heart rate relieves ischaemia
Decreased workload
Decreased O2 demand
Preserved O2 supply
IschIschaaemiaemia
Increased diastolic time
Decreased heart rate
Angina Severity and Mortality
Spertus JA, et al. Circulation. 2002;106:43-9
1 ye
ar m
orta
lity
rate
SAQ=Seattle Angina Questionnaire
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 ratein 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 J Postgrad Med J 2010;86:212-217.2010;86:212-217.
A Diaz et al. EHJ 2005; 26: 976-74
IV. Role of heart rate in
acute coronary syndrome
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
High Heart Rates are Predictive of Coronary Plaque Ruptures
Heidland UE, Strauer BE. Circulation. 2001;104:1477-1482. AS-ct11-0706
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
HR<96 HR<96 96-12 113-133 96-12 113-133 >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 0 0
70–89 70–89 77
90–109 90–109 13 13
110–149 110–149 2323
150–199 150–199 36 36
>200 >200 4646
Systolic BP (mmHg)Systolic BP (mmHg)
Creatinine (mg/dL)Creatinine (mg/dL)
Killip classKillip class
Cardiac arrest at Cardiac arrest at admission Elevated admission Elevated cardiac markers ST-cardiac markers ST-segment deviationsegment deviation
GRACE scoreGRACE score for risk prediction in patients with ACS for 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
V. Role of heart rate in
Postmyocardial infarction
All cause mortality
Sudden cardiac death
HR variability
LVEF
HRmean
Sensitivity
Spe
cific
ity
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.
Kjekshus JK. Eur Heart J. 1985;6:A29. Am J Cardiol 1986;57:43F
Early interventionAMI size r=0.97
Post AMIMortality r=0.79Reinfarction r=0.59
R=0.79P<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.
PropranololAtenolol
Timolol
Metoprolol
Metoprolol
Propranolol
-4 -8 -12 -16 -20
Reduction in heart rate (min-1)
-30
-20
-10
Reduction ininfarct size (%)
Kjekshus JK. Am J Cardiol. 1986;57:43F-49F.
Lowering heart rate reduces infarct size in MI
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
1.91.93.93.9
9.39.3
20.220.2
1010
2020 n=11020
6-month mortality
10 times
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
HR HR (bpm)(bpm)
Rel
ativ
e ris
k (lo
g)
0.1
0.2
0.5
1.0
2.0
-5 -10 -15 -200
P<0.001P<0.001
VI. High resting heart rate
in chronic heart failure
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)
High resting heart rate is an independent predictor of death in patients with heart failure
Lechat P. CIBIS II. Circulation. 2001:103:1428-1433.
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
XAMOTEROLPROFILE
PROMISE
VHeFT(HDZ/ISDN)SOLVD
CONSENSUS
ANZ
VHeFT(prazosin)
US CARVEDILOL
BHATCIBIS
NORTIMOLOL
MOCHA
GESICA
Change in mortality (%)
Change in heart rate (bpm)Kjekshus et al. Eur Heart J. 1999 (suppl), H64-H69
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
American College of Cardiology / American Heart Association
ACC/AHA guidelines. 2002.
Lowering heart rate???new treatment option
A key objective to save livesin both CAD & heart failure
With WHAT & HOW we should lower it?
Heart rate lowering with Heart 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)
xxxx xx
xx
xxxx
xx xxxx xx
xx
44
33
22
11
Daily frequency of ischemic episodesDaily frequency of ischemic episodes
Stone PH, Circulation 1990;82:1962-1972
Sir James BlackBritish 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
Effects of beta-blockers
= Reduces heart rate
= Reduces LV contraction
= Reduces conduction
= Reduces blood pressure
= Prevents coronary vasodilatation during exercise
Limitation of BETA-BLOCKERSLimitation of BETA-BLOCKERSHard 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
Are there anything more than beta-blockers?
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– Cinquième niveau
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Lowering heart rate???new treatment option
A key objective to save livesin both CAD & heart failure
with Ivabradine:
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
Ivabradine: pure heart rate reduction
If inhibition reduces the diastolic depolarization slope and thereby lowers heart rate
RR
Pureheart ratereduction
0 mV
-40 mV
-70 mV
Thollon C, et al. Brit J Pharmacol. 1994;112:37-42.
closedopen
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
0
-5
-10
-15
bpm
Ivabradine (mg)
5 bid 7.5 bid
Atenolol (mg)
50 od 100 odn=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
-40
-30
-20
-10
0
10
40 50 60 70 80 90 100 110 120
Baseline HR (bpm)
H
F fro
bas
elin
e (b
pm)
5 mg bid
7.5 mg bid
Heart Rate Reduction by Ivabradine is Dependent on Baseline Heart Rate
(n=720): Safety Relevance!
Anti-ischemic efficacy of Ivabradine
compared to beta blockers
INITIATIVE
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-out2-7 days
Run-in7 days
Run-out14 days1 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
00
11
22
33
44
AAtenololtenolol 100 mg 100 mg
Reduction in number of angina attacks Reduction in number of angina attacks (after 4-month treatment)(after 4-month treatment)
Bas
elin
e
Bas
elin
e
Antianginal efficacy of Ivabradine
Ivabradine Ivabradine 7.5 mg7.5 mg
Tardif JC, et al. Eur Heart J. 2005;26:2529-2536.
Number/weekNumber/week
- 70%- 72%
INITIATIVE
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
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-segmentdepression
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
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
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
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
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
IvabradineIvabradine7.5 mg bid 7.5 mg bid
Tardif JC, et al. Eur Heart J. 2009;30:540-548.
Heart rate (bpm)
58
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
“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).
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%
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)
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 or molsidomine or
L-A nitratesL-A nitratesNo dataNo data
At trough of drug activity
*Standard Bruce Protocol
**Modified Bruce
-70
-60-50-40-30-20-10
0Ove
rall
Wom
en
Previou
s MI*
Previou
s PTCA*
Previou
s CABG*
Diabete
s
Asthma/C
OPD*
PVD*
Age >6
5 yea
rs
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 Attacks
Change in angina attacks from baseline (%)
Does It Work in Clinical Practice?Does It Work in Clinical Practice?ADDITIONSADDITIONS STUDYSTUDY
• 2,230 2,230 Stable Stable angina angina patients, HR patients, 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 of On top of BBBB• 4 months 4 months treatmenttreatment• Parameters recordedParameters recorded
1.Heart Rate 2.Angina attacks 3.Nitrate consumption4.Tolerance5.QOL
Design of addition studyDesign of addition study
Werdan K, et al. Clin Res Cardiol. 2012.
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
0.80.4
Baseline 1 Month 4 Months
P<0.001 for all differences
Ivabradine in combination with beta-blockers Ivabradine in combination with beta-blockers improves symptoms in angina patients improves symptoms in angina patients
Effect of Ivabradine on
Morbi-mortality in CAD
Angina
Evidences of Ivabradine
MorBidity-mortality EvAlUation of The I f inhibitor
ivabradine in patients with coronary disease and
left ventricULar dysfunction
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
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
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
Values in parentheses are standard deviations
PlaceboPlacebo ivabraineivabraine
Male, % Male, % 8383 8383 8383
Age, years Age, 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
Optimal preventive therapyOptimal preventive therapy
Study Therapy Aspirin orantithrombotic
(%)
Statins
(%)
BB
(%)
RASagents
(%)
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 therapyRevascularization
95 89 89 65
REACH CAD Registry 93 76 62 8BEAUTIFUL 2008 CAD + LVD ivabradine 94 74 87 90
Patients
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
HR as inclusionHR as inclusion ≥ 60 bpm Average Average 71 bpm71 bpm
Mean HR reduction(Patients with baseline HR ≥ 70 bpm)
Heart rate (bpm)
65
7573
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
Effect of ivabradine on the primary endpoint (overall population)
Effect of ivabradine on the primarycomposite endpoint (HR ≥ 70 bpm)
Effect of ivabradine in patients with HR ≥70 bpm
coronary revascularization
hospitalization for MI
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%
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 anginaor revascularization
0.00136%0.64Fatal and nonfatal MI
P valueRiskreduction
Hazardratio
Predefined end point
Ivabradine reduces coronary risk in stable coronary patients with HR ≥ 70 bpm
Fox et al .Lancet. 2008;372:807-816.
Secondary prevention of myocardial Secondary prevention of myocardial infarction in stable CAD infarction in stable CAD
NNT-1
Number needed to treat to prevent one event per 1 year (NNT-1) Study Event
ACE inhibitorsACE inhibitors
Statins Statins
Ivabradine
Scandinavian Simvastatin Survival Study (4S)1
63 patientsMajor 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;342:145-1533- Fox K, et al. Lancet. 2008;372:807-816.
RanolazineRanolazine
TrimetazidineTrimetazidine
-Blockers-Blockers
Calcium antag.Calcium antag.
NitratesNitrates
NicorandilNicorandil
Ivabradine
Improvedtime to onset
of ST-segmentdepression
++
++
++
++
++
++
+
Decreasein anginalepisodes
++
++
++
++
++
++
+
Improvedtotal
exerciseduration
++
++
++
++
++
++
+
Reducedrevascularization
NANA––
––++
––
NANA+
Preventionof MI
NANA––
––––––
––
+
Improvedsurvival
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
New evidence from
ESC’09
Breaking
News
A subgroup analysis in patients with limiting anginalimiting angina
at baseline
AnginaAngina
Patients with angina and follow-up
1507 randomizedwith angina
734 to Ivabradine 773 to placebo
773 analyzed734 analyzed
12 138 screened
10 917 randomized
Angina
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 resultsAngina
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 20
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
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 20
5
10
15
0.5 1 1.5 2
Ivabradine reduces hospitalization for MI
* Fatal and nonfatal eventsFox 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
x
x
BradycardiaHypotensionNegative inotropic effectPeripheral vasoconstrictionIncrease coronary resistanceBronchospasmDecrease to insuline responseFatigueDepressionSleep disturbancesErectile dysfunctionLower limbs oedemaConstipationVisual effects
xxx xxxxxxxx
x+/-
xxxx
xx
BB CCB Ivabradine
Ivabradine free from the side-effects of the -blockers and Calcium-channel-blockers
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
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
Effect of Ivabradine on
Morbi-mortality in AMI
Evidences of Ivabradine
Systolic Heart failure treatment withthe If inhibitor ivabradine Trial
Primary objective
To evaluate whether the To evaluate whether the IIff inhibitor ivabradine inhibitor ivabradine
improves improves cardiovascular outcomescardiovascular outcomes
in patients with in patients with moderate to severemoderate to severe chronic heart failure chronic heart failure
(LVEF (LVEF 35%) 35%) & & Heart rate Heart rate 70 bpm70 bpm, ,
on top of best recommended therapyon top of best recommended therapy
EUROPEGermany Portugal
Belgium Greece SpainDenmark Ireland SwedenFinland Italy TurkeyFrance The Netherlands UK
BulgariaCzech RepublicEstoniaHungary
South AmericaArgentinaBrazilChili
North AmericaCanada
ASIAChinaHong KongIndiaSouth KoreaMalaysia
Australia
LatviaLithuaniaNorwayPolandRomania
RussiaSlovakiaSloveniaUkraine
The largest Heart Failure trial
6505 patients, 37 6505 patients, 37 countriescountries, 677 , 677 centrescentres
ASIA : 520 pts
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.
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-blockers In total population and in patients with at least 50% target dose of beta-blockers
Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.
Baseline characteristics
IvabradineIvabradine32413241
PlaceboPlacebo32643264
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.
Mean heart rate reduction
70% of patients70% of patients on ivabradine 7.5 mg bid on ivabradine 7.5 mg bid
0 2 weeks 1 4 8 12 16 20 24 28 32MonthsMonths
90
80
70
60
50
67
7575
80
64
Heart rate (bpm)Heart rate (bpm)
Placebo
Ivabradine
Swedberg K, et al. Lancet. 2010;online August 29.
- 8 bpm
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
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 (%)
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 (%)
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%) ??
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
00 6 12 18 24 30 Months
≥87 bpm
80 to <87 bpm
75 to <80 bpm
72 to <75 bpm70 to <72 bpm
P<0.001
Patients with primary composite endpoint (%)
Böhm et al, Lancet 2010; 376: 886-894.
Prospective Study
Baseline heart rate is a predictor of endpoints on placebo
50
40
30
20
10
00 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 bpm72 to <75 bpm70 to <72 bpm
50
40
30
20
10
00 6 12 18 24 30
Months
Cardiovascular death (%)
P<0.001
Böhm et al, Lancet 2010; 376: 886-894.
Benefit of ivabradine in all prespecified subgroups
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.
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)
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
Conclusion
• HF with with 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
Morbidity benefit of Ivabradine in Heart Failure
compared to beta blockers
CARVIVA HF
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
ScreeningBaseline
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
CARVIVA primary endpoint: Change in CARVIVA primary endpoint: Change in exercise capacityexercise capacity
% c
hang
e co
mpa
red
to b
asel
ine
*P<0.01 vs baseline. †P<0.01, ††P<0.02 vs carvediolol
*†
*†† *††
*†
Volterrani et al. Int. J. Cardiol. 2011;151:218-224
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
Morbidity benefit of Ivabradine in Heart
Failure on top of optimal treatment
The INTENSIFY study: practical daily The INTENSIFY study: practical daily effectiveness and tolerance of ivabradine in effectiveness 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.
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.
+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.
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.
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
Effect of Ivabradine on Morbi-mortality in
CAD with normal LV function
Evidences of Ivabradine
Ivabradine Starting dose 7.5 mg bid
Placebo bid
Run in2 - 4 weeks
M006M003M000 Every 6 months
Target HR: 55-60 bpm
MethodsEvents: 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%
PopulationOutpatients with stable CAD without LVSD (EF > 40%) or clinical signs of HF, with appropriate CV medication
95% CI [-10.0; -9.5]
9.7 bpm
ConsiderationsFirst: 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
• 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
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
Morbi-mortality benefit ofheart rate lowering depends on LV function
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.
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
Oct 2015-Angina not improved- advised for revascularization- declined
5 pm,8.5 2016- Severe angina, BP-80/60admitted to CCU MGH
Omit BB, ACEIIV Doubtamine
8 am, 9.5 2016- Still angina, BP-110/70, orthopnoeic, pul oedema
IV DoubtamineIV GTNIV Lasix
11.5 2016- free of angina, BP-120/70, can lie in flat
Added Ivabradine 5mg BDUptitrated to 7.5mg BD next day
14.5 2016- free of angina, BP-120/70, oral Lasix, awaiting for angio
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
Ivabradine preserves global cardiac function
Myocardial contractility Preserved1
Preserved2Ventricular 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
Pharmacological therapy for CHF patients
1. Diuretics
2. ACEI/ARB
3. Beta-blocker
4. Heart rate lowering
- Digoxin
- Ivabradine
Evidences of Ivabradine across Cardiovascular Continuum
Remodeling
Ventricular Dilation
Chronic Heart Failure
Myocardial Ischemia (angina)
AtherosclerosisLVH
Coronary Artery Disease
Coronary Thrombosis Arrhythmi
as
End-StageHeart Disease,Death
DyslipidemiaHypertensionDiabetesSmokingObesity
Myocardial Infarction
The Cardiovascular
Continuum
Dzau V et al. Circulation. 2006;114:2850-2870
INITIATIVEINITIATIVE
Stable CAD & Normal EF
CARVIVA HF
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
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
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