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Heart rate The Lower The Better. HEART RATE. CONSIDERATIONS IN CARDIOVASCULAR DISEASE. 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

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heart rate

HEART RATE

CONSIDERATIONS IN CARDIOVASCULAR DISEASE

slide3

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.

hypothesis
Hypothesis
  • High heart rate adversely affects prognosis in health and disease
  • Treatment to reduce heart rate improves prognosis
slide5

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 2006;24 3) Perski, AHJ 1992, 4) Heidland, Circulation 2001, 5) Brown BG, Circulation 1993, 6)Heusch G, Yoshimoto N. Arc. 1983

life expectancy and heart rate in the animal kingdom
Life expectancy and heart rate in the animal kingdom
  • 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]”

Small animals must produce more heat (↑ Mass : BSA ratio).

Thus higher metabolic rate and heart rate

1000

Levine JACC 1997

600

mouse

hamster

rat

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

heart rate and life duration

HR : 6 beats/min

HR : 600 beats/min

Expected life duration :

177 years

Expected life duration :

2 years

Heart Rate and Life Duration

Comparable number of heart beats across species during a lifetime

slide8

Heart rate and myocardial oxygen consumption

20

20

20

DOG 4

DOG 6

DOG 5

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 6

DOG 5

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

slide9

Heart rate increase. Associated with:

  • Increase sympathetic tone
  • Poor fitness
  • Impaired ventricular function
  • Cluster of risk factors
slide10

Heart rate increase - Detrimental effects

  • Increase MVO2
  • Reduce diastole / (coronary flow)
  • Decrease fibrillation threshold
  • Atherogenic effect
  • Plaque rupture
  • Induces myocardiopathy
  • Other
the british regional heart study
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

>60

60-69

70-79

80-89

>90

Heart rate (bpm)

Shaper BHJ 1993

slide12

24.913

Men/women

Suspected

or proved

CAD

14.7 y

Follow-up

CASS

Eur Heart J

2005;26:967

slide13

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

1990;65:547

slide14

Heart rate and atherosclerosis: angiographically visible collaterals

Heart rate

<60 beats/min

P<0.05

Collaterals

Heart rate

>60 beats/min

Patel et al., Coron Artery Dis11:467-472, 2000

slide15

Heart rate and coronary plaque rupture

Heidland and Strauer, Circulation 2001;104:1477

slide16

Post-MI mortality and heart rate (n=1807)

Maximum heart rate

Final heart rate

50

50

40

40

30

30

Mortality (%)

Mortality (%)

20

20

10

10

0

0

<50

5059

6069

7079

8089

9099

100109

110119

≥120

<50

5059

6069

7079

8089

9099

≥100

Heart Rate (bpm)

Heart Rate (bpm)

Hjalmarson et al, Am J Cardiol 1990;65: 547-553.

slide17

Increased heart rate shortens Life

GRACE 6 month Risk Score for ACS

JAMA. 2004;291:2727

slide18

Increased heart rate shortens Life

HR at discharge an 6 months mortality

Myocardial

Infarction

6 months

Follow-up

%

GISSI-3

Eur Heart J

1999;H52

slide19

Relationship between Heart Rate and Heart Failure

COMET

Heart Rate after 4 months of treatment with Beta-blockers

 68 bpm

> 68 bpm

All cause mortality

Reduced risk

Increased risk

0.50 0.75 1.00 1.25 1.50

Relative risk (95% CI)

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. 2005;26:2259-2268.

slide20

CIBIS II

One-year mortality (%)

n=2539

18

16

14

12

10

8

6

4

Bisoprolol

2

Placebo

0

> 84 bpm

72 bpm

72 to 84 bpm

Baseline Heart Rate

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. 2001;13:1428-1433.

slide21

1

O

0

Death Log Risk Ratio

O

-1

O

-2

O

-3

-20

-15

-10

-5

Heart Rate Reduction (beats/min)

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 2009;150:784-794

slide23

Baseline heart rate is a predictor of endpoints on placebo

Patients with primary composite endpoint (%)

50

≥87 bpm

P<0.001

40

80 to <87 bpm

75 to <80 bpm

30

72 to <75 bpm

70 to <72 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

P<0.001

40

40

≥87 bpm

P<0.001

30

≥87 bpm

30

80 to <87 bpm

75 to <80 bpm

80 to <87 bpm

20

20

72 to <75 bpm

75 to <80 bpm

70 to <72 bpm

72 to <75 bpm

70 to <72 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.

slide24

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

<60

60 to <65

65 to <70

70 to <75

<60

60 to <65

65 to <70

70 to <75

≥75

≥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.

slide25

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. 2010;online August 29.

slide26

Primary composite endpoint according to heart rate achieved at D28* in the ivabradine group

50

40

30

20

10

0

0

Day 28

6

12

18

24

30

Patients with primary composite endpoint (%)

≥75 bpm

70-<75 bpm

60-<65 bpm

65-<70 bpm

<60 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.

primary composite endpoint

Ivabradine

Placebo

Ivabradine n=793 (14.5%PY) Placebo n=937 (17.7%PY)

HR = 0.82 p<0.0001

Primary composite endpoint

Cumulative frequency (%)

40

- 18%

30

20

10

NNT = 26

0

0

6

12

18

24

30

Months

Swedberg K, et al. Lancet. 2010;online August 29.

slide28

Ivabradine

Placebo

Hospitalization for heart failure

Ivabradine n=514 (9.4%PY) Placebo n=672 (12.7%PY)

HR = 0.74 p<0.0001

Cumulative frequency (%)

30

- 26%

20

10

NNT = 27

0

0

6

12

18

24

30

Months

Swedberg K, et al. Lancet. 2010;online August 29.

slide29

Death from heart failure

Cumulative frequency (%)

10

HR = 0.74 (0.58–0.94)

P = 0.014

Placebo

26%

5

Ivabradine

0

0

6

12

18

24

30

Months

Swedberg K, et al. Lancet. 2010;online August 29.

slide30

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 (%)

31

33.7

29.7

22.5

20.7

17.2

HR 70 bpm

HR >75 bpm

HR >80 bpm

slide31

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

Hazard ratio

3.5

40

3.0

40

3.0

Estimated hazard ratio

2.5

2.5

30

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

< 50

> 100

> 80 to < 85

> 50 to < 55

≤ 50

> 90 to < 95

> 60 to < 65

> 65 to < 70

> 55 to < 60

> 75 to < 80

> 85 to < 90

> 100

> 70 to < 75

> 95 to < 100

> 85 to ≤ 90

> 50 to ≤ 55

> 65 to ≤ 70

> 80 to ≤ 85

> 70 to ≤ 75

> 75 to ≤ 80

> 60 to ≤ 65

> 55 to < 60

> 90 to ≤ 95

> 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. 2008;29:1327-34.

slide32

1.0

0.9

0.8

0.7

0.6

0.5

≤62

63-70

5

10

15

20

0

71-76

77-82

≥83 bpm

Epidemiologic Evidence

Coronary Artery Disease

Adjusted survival curves for overall mortality

P<0.0001

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

Cumulative survival

Years after enrolment

Diaz A, et al. Eur Heart J 2005;26:967-974

slide33

MorBidity-mortalityEvAlUation of The If inhibitor ivabradine in paients with CAD and left ventricULar dysfunction.

slide34

0

0.5

1

1.5

2

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 < 70 bpm

0

Years

Analysis from the BEAUTIFUL placebo arm

Fox K et al. Lancet 2008;372:779-780

slide35

0

0.5

1

1.5

2

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 < 70 bpm

2

0

Years

Analysis from the BEAUTIFUL placebo arm

Fox K et al. Lancet 2008;372:779-780

slide36

0

0.5

1

1.5

2

Heart rate as a predictor ofhospitalization for HF

15

Hazard ratio = 1.53 (1.25 – 1.88)

Heart rate ≥ 70 bpm

P < 0.0001

10

% with hospitalization for fheart failure

5

Heart rate < 70 bpm

0

Years

Analysis from the BEAUTIFUL placebo arm

Fox K et al. Lancet 2008;372:779-780

slide37

0

0.5

1

1.5

2

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 < 70 bpm

0

Years

Analysis from the BEAUTIFUL placebo arm

Fox K et al. Lancet 2008;372:779-780

slide38

Epidemiologic Evidence

Hypertension

60

CHD

50

CVD

All cause

40

Age-adjusted 2-year rate per 1000

30

20

10

0

< 65

65-74

75-84

> 84

Heart Rate (bpm)

Framingham Study

Gillman MW, et al. Am Heart J 1993;125:1148

slide39

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.

slide40

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 2006;24:603-610

slide41

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?
slide42

Questions

How applicable is this data to my everyday practice?

Is treating to target beta-blocker dose the answer?

Is it important how we lower the heart rate?

slide43

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?