Heart rate The Lower The Better

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Heart rateThe Lower The Better
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HEART RATE

• CONSIDERATIONS IN CARDIOVASCULAR DISEASE

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Heart rate new paradigm
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
Ferrari et al., Eur Heart J 2008, 10(Suppl)
F7-10.
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Hypothesis

• High heart rate adversely affects prognosis in
  health and disease
• Treatment to reduce heart rate improves prognosis

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Detrimental effects of increased HR

• Increased MVO21
• Reduced diastole/coronary flow1,6,
• Decrease fibrillation threshold1
• Atherogenic effect2,3,4
• Plaque rupture5
• Induces cardiomyopathy1
• Decrease in LV ejection fraction
• Decrease arterial compliance1

1) Kjekshus J, EHJ suppl 1999, 2) Yamamoto E, J
Hypertens 200624 3) Perski, AHJ 1992, 4)
Heidland, Circulation 2001, 5) Brown BG,
Circulation 1993, 6)Heusch G, Yoshimoto N. Arc.
1983
6
Life expectancy and heart rate in the animal
kingdom
Small animals must produce more heat (? Mass
BSA ratio). Thus higher metabolic rate and heart
rate
1000
Levine JACC 1997
600
mouse
hamster
rat

• 40 fold difference in life expectancy
• Number of heart beats / lifetime is constant (7.3
  5.6 x 108)
• life span is predetermined by basic energetics
  of living cells and heart rate is a main
  determinant of life span

300
Heart rate bpm
monkey
marmot
cat
dog
100
giraffe
man
tiger
ass
50
horse
lion
elephant
whale
20
whale
20
40
60
80
Life expectancy, yrs
Levine JACC 1997
7
Heart Rate and Life Duration
Comparable number of heart beats across species
during a lifetime
8
Heart rate and myocardial oxygen consumption
20
20
20
DOG 4
DOG 5
DOG 6
Myocardial oxygen consumption (ml/min/100g)
10
10
10
0
0
0
100
200
100
200
100
200
0.1
0.1
0.1
DOG 4
DOG 5
DOG 6
Myocardial oxygen consumption (ml/beat/100g)
0.05
0.05
0.05
0
0
0
100
200
100
200
100
200
Heart rate (min-1)
Tanaka et al., Jap J Physiol 40 503-521, 1990
9

• Heart rate increase. Associated with
• Increase sympathetic tone
• Poor fitness
• Impaired ventricular function
• Cluster of risk factors

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• Heart rate increase - Detrimental effects
• Increase MVO2
• Reduce diastole / (coronary flow)
• Decrease fibrillation threshold
• Atherogenic effect
• Plaque rupture
• Induces myocardiopathy
• Other

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The British Regional Heart Study
IHD major events

• 7735 males 40-59 yrs
• 8 year follow up
• No pre-existing IHD
• Strong association between resting HR and SCD
  and IHD (major events mortality)

IHD mortality
10
Sudden Cardiac Death
8
Age adjusted rate per 1000 per year
6
4
2
gt60
60-69
70-79
80-89
gt90
Heart rate (bpm)
Shaper BHJ 1993
12
24.913 Men/women Suspected or proved CAD 14.7
y Follow-up
CASS Eur Heart J 200526967
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Increased heart rate shortens Life
Mortality, from hospital discharge to 1 year
n 1807 Myocardial Infarction M W 45 - 55 y 1
y Follow-up
Hjalmarson A Am J Cardiol 199065547
14
Heart rate and atherosclerosis angiographically
visible collaterals
Heart rate lt60 beats/min
Plt0.05
Collaterals
Heart rate gt60 beats/min
Patel et al., Coron Artery Dis11467-472, 2000
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Heart rate and coronary plaque rupture
Heidland and Strauer, Circulation 20011041477
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Post-MI mortality and heart rate (n1807)
Maximum heart rate
Final heart rate
50
50
40
40
30
30
Mortality ()
Mortality ()
20
20
10
10
0
0
lt50
5059
6069
7079
8089
9099
100109
110119
120
lt50
5059
6069
7079
8089
9099
100
Heart Rate (bpm)
Heart Rate (bpm)
Hjalmarson et al, Am J Cardiol 199065 547-553.
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Increased heart rate shortens Life
GRACE 6 month Risk Score for ACS
JAMA. 20042912727
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Increased heart rate shortens Life
HR at discharge an 6 months mortality
Myocardial Infarction 6 months Follow-up

GISSI-3 Eur Heart J 1999H52
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Relationship between Heart Rate and Heart Failure
The benefits of Beta-Blocker therapy in Heart
Failure patients are related to their ability to
decrease Heart Rate
Metra M, et al. Eur Heart J. 2005262259-2268.
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Relationship between Heart Rate and Heart Failure
Heart Failure patients with a higher baseline
Heart Rate have a greater risk of dying
CIBIS II. Lechat P, et al. Circulation.
2001131428-1433.
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Meta analysis BB dose, Heart Rate Reduction
and Death in patients with Heart Failure
Meta-regression of 23 beta-blocker HF trials
involving 19,209 patients Mortality benefit was
related to magnitude of HR reduction and not to
the dose of BB. Pooled Mortality Hazard Ratio was
0.76 for an average HR Reduction 12 bpm
McAlister et al Ann Intern Med 2009150784-794
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Systolic Heart Failure treatment with the If
Inhibitor Procoralan Trial
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Baseline heart rate is a predictor of endpoints
on placebo
Patients with primary composite endpoint ()
50
87 bpm
Plt0.001
40
80 to lt87 bpm
75 to lt80 bpm
30
72 to lt75 bpm
70 to lt72 bpm
20
10
Months
0
0
6
12
18
24
30
Primary composite endpoint risk increases by 3
per 1bpm increase, and by 16 per 5bpm increase
Patients with first hospital admission for HF ()
Patients with cardiovascular death ()
50
50
Plt0.001
40
40
87 bpm
Plt0.001
30
30
87 bpm
80 to lt87 bpm
75 to lt80 bpm
80 to lt87 bpm
20
20
72 to lt75 bpm
75 to lt80 bpm
70 to lt72 bpm
72 to lt75 bpm
70 to lt72 bpm
10
10
Months
0
0
Months
0
6
12
18
24
30
0
6
12
18
24
30
Bohm M et al. The Lancet, published online August
29, 2010.
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Distribution of patients by classes of heart rate
achieved at D28
Ivabradine
Placebo
Patients in heart rate group ()
Patients in heart rate group ()
50
50
40
40
30
30
20
20
10
10
0
0
70 to lt75
65 to lt70
60 to lt65
lt60
75
70 to lt75
65 to lt70
60 to lt65
lt60
75
Heart rate achieved at day 28 (bpm)
Heart rate achieved at day 28 (bpm)
Data exclude patients reaching primary composite
endpoint in the first 28 days
Bohm M et al. The Lancet, published online August
29, 2010.
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• To evaluate whether theIf inhibitor ivabradine
  improves cardiovascular
• outcomes in patients with moderate to severe
• chronic heart failure, reduced
• left ventricular ejection fraction and heart rate
  ? 70 bpm
• receiving recommended therapy

Swedberg K, et al. Lancet. 2010online August 29.
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Primary composite endpoint according to heart
rate achieved at D28 in the ivabradine group
Patients with primary composite endpoint ()
75 bpm
70-lt75 bpm
60-lt65 bpm
65-lt70 bpm
lt60 bpm
Months
Data exclude patients reaching primary composite
endpoint in the first 28 days
Bohm M et al. The Lancet, published online August
29, 2010.
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Primary composite endpoint
Ivabradine n793 (14.5PY) Placebo n937
(17.7PY) HR 0.82 plt0.0001
Cumulative frequency ()
40
- 18
30
20
10
NNT 26
0
0
6
12
18
24
30
Months
Swedberg K, et al. Lancet. 2010online August 29.
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Hospitalization for heart failure
Ivabradine n514 (9.4PY) Placebo n672 (12.7PY)
HR 0.74 plt0.0001
Cumulative frequency ()
30
- 26
20
10
NNT 27
0
0
6
12
18
24
30
Months
Swedberg K, et al. Lancet. 2010online August 29.
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Death from heart failure
Cumulative frequency ()
10
HR 0.74 (0.580.94) P 0.014
Placebo
26
5
Ivabradine
0
0
6
12
18
24
30
Months
Swedberg K, et al. Lancet. 2010online August 29.
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HF registries more than 50 of patients have
heart rate ?70 bpm
IMPACT RECO III 1407 patients
HF OUTCOME 3480 patients
ESC PILOT HF 2450 patients
54.6
55.6
53.4
Patients ()
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33.7
29.7
22.5
20.7
17.2
HR ?70 bpm
HR gt75 bpm
HR gt80 bpm
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CV events are directly related to resting HRin
patients with CAD and hypertension
60
4.5
Outcome (all-cause death, non fatal MI, or non
fatal stroke)
60
4.5
4.0
Outcome (all-cause death, non-fatal MI, or
nonfatal stroke)
50
4.0
Hazard ratio
3.5
50
3.5
Hazard ratio
40
3.0
40
3.0
Estimated hazard ratio
2.5
2.5
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Adverse outcome incidence ()
Estimated hazard ratio
30
Adverse outcome incidence ()
2.0
2.0
20
20
1.5
1.5
1.0
10
1.0
10
0.5
0.5
0
0
0
0
lt 50
gt 100
gt 80 to lt 85
gt 50 to lt 55
gt 90 to lt 95
50
gt 60 to lt 65
gt 65 to lt 70
gt 55 to lt 60
gt 85 to lt 90
gt 75 to lt 80
gt 70 to lt 75
gt 95 to lt 100
gt 100
gt 50 to 55
gt 55 to lt 60
gt 60 to 65
gt 65 to 70
gt 80 to 85
gt 85 to 90
gt 70 to 75
gt 75 to 80
gt 90 to 95
gt 95 to 100
Mean follow-up heart rate (bpm)
Mean follow-up heart rate (bpm)
INVEST study, 22 192 CAD patients 2.7-year
follow-up
Kolloch et al., Eur Heart J. 2008291327-34.
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Epidemiologic Evidence Coronary Artery Disease
Adjusted survival curves for overall mortality
Plt0.0001

• CASS registry
• 24 913 CAD patients
• 14.1-year follow-up

Cumulative survival
Years after enrolment
Diaz A, et al. Eur Heart J 200526967-974
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MorBidity-mortality EvAlUation of The If
inhibitor ivabradine in paients with CAD and left
ventricULar dysfunction.
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Heart rate as a predictor ofcardiovascular death
15
Hazard ratio 1.34 (1.10 1.63)
Heart rate 70 bpm
P 0.0041
10
with cardiovascular death
5
Heart rate lt 70 bpm
0
Years
Analysis from the BEAUTIFUL placebo arm
Fox K et al. Lancet 2008372779-780
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Heart rate as a predictor ofhospitalization for
MI
8
Hazard ratio 1.46 (1.11 1.91)
Heart rate 70 bpm
P 0.0066
6
with hospitalization for fatal non-fatal MI
4
Heart rate lt 70 bpm
2
0
Years
Analysis from the BEAUTIFUL placebo arm
Fox K et al. Lancet 2008372779-780
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Heart rate as a predictor ofhospitalization for
HF
15
Hazard ratio 1.53 (1.25 1.88)
Heart rate 70 bpm
P lt 0.0001
10
with hospitalization for fheart failure
5
Heart rate lt 70 bpm
0
Years
Analysis from the BEAUTIFUL placebo arm
Fox K et al. Lancet 2008372779-780
37
Heart rate as a predictor ofcoronary
revascularization
6
Hazard ratio 1.38 (1.02 1.86)
P 0.037
Heart rate 70 bpm
4
with coronary revascularization
2
Heart rate lt 70 bpm
0
Years
Analysis from the BEAUTIFUL placebo arm
Fox K et al. Lancet 2008372779-780
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Epidemiologic Evidence Hypertension
60
CHD
50
CVD
All cause
40
Age-adjusted 2-year rate per 1000
30
20
10
0
lt 65
65-74
75-84
gt 84
Heart Rate (bpm)
Framingham Study
Gillman MW, et al. Am Heart J 19931251148
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Conclusions

• Heart rate is linked (epidemiologically) to long
  term outcomes in a variety of cardiovascular
  conditions.
• Heart rate is predictive of outcomes in ischaemic
  heart disease and in heart failure.
• Heart rate is a modifiable risk factor in
  ischaemic heart disease and in heart failure.
• It is important to be cognisant of heart rate in
  cardiac patients, and endeavor to lower the rate
  to below 70 bpm where possible.
• Ivabradine, on top of beta blocker therapy, gives
  additional benefit in cardiac patients with heart
  failure.

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Is heart rate a risk marker or a risk factor?

• Positive association with total and/or
  cardiovascular mortality in 37 out of 39 studies.
• Association independent of other risk factors for
  atherosclerosis or cardiovascular events.
• Consistency similar to that for smoking.
• Association present in different clinical
  settings and in subjects with or without
  co-morbidities.
• Association present at all ages.
• Association still present after exclusion of
  first years after baseline evaluation.
• Association less consistent for women.

Palatini P, et al. J Hypertension 200624603-610
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The prognostic validity of resting heart rate

• Are prognostic data consistent? Is heart rate an
  independent riskmarker/risk factor?
• Is association valid in both genders, in elderly,
  in differentethnicities?
• Can resting heart rate be used to assess risk in
  patients andpopulations with coronary artery
  disease?
• Is heart rate related to known pathophysiologic
  mechanisms ofcoronary artery disease?
• Is there evidence of clinical outcome benefit
  associated withheart rate reduction?

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Questions

1. How applicable is this data to my everyday
   practice?
2. Is treating to target beta-blocker dose the
   answer?
3. Is it important how we lower the heart rate?

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Heart Rate Reduction - A Therapeutic Target

• Heart rate and life expectancy - population
  studies
• All cause mortality
• Cardiovascular disease
• Cancer
• Age and gender effects
• Heart rate and prognosis in established heart
  disease
• Stable CAD
• AMI
• CCF
• Diabetes
• Heart rate reduction and prognosis a new
  therapeutic target?