the pivotal role of heart rate in cardiovascular disease

The pivotal role of heart rate The pivotal role of heart rate in cardiovascular diseasein cardiovascular disease

AtherosclerosisAtherosclerosis

Endothelial dysfunction↑Endothelial dysfunction↑

Oxidative stress↑Oxidative stress↑

Plaque stability↓Plaque stability↓

Arterial stiffness↑Arterial stiffness↑

IschemiaIschemia

Oxygen consumption↑Oxygen consumption↑

Duration of diastole↓Duration of diastole↓

Coronary perfusion↓Coronary perfusion↓

RemodelingRemodeling

Cardiac hypertrophy↑Cardiac hypertrophy↑

Chronic heart failureChronic heart failure

Oxygen demand↑Oxygen demand↑

Ventricular efficiency ↓Ventricular efficiency ↓

Ventricular relaxation↑Ventricular relaxation↑

Elevated heart rateElevated heart rate

+

+ +

+

The role of heart rate in cardiovascular diseaseThe role of heart rate in cardiovascular disease

Positive association with total and/or cardiovascular mortality Positive association with total and/or cardiovascular mortality

Association independent of other cardiovascular risk factors Association independent of other cardiovascular risk factors

Association valid in both genders, in the elderly, in differentAssociation valid in both genders, in the elderly, in different

ethnicities ethnicities

A strong predictor of mortality in patients with coronary artery A strong predictor of mortality in patients with coronary artery

disease disease

Relation to known pathophysiologic mechanisms ofRelation to known pathophysiologic mechanisms of

coronary artery diseasecoronary artery disease

Clinical outcome benefit associated with heart rate reductionClinical outcome benefit associated with heart rate reduction

The prognostic validity of resting heart rateThe prognostic validity of resting heart rate

The first evidence of the prognostic importanceThe first evidence of the prognostic importanceof heart rate: 1945of heart rate: 1945

Levy RL et al. JAMA. 129 (1945): 585-588.

Age (years)

Rat

e p

er 1

000

pers

on-y

ears

Transienttachycardia

––++

Transienthypertension

–+–+

0

10

20

30

40

50

60

70

25 30 35 40 45 50 55 60

Prognostic importance of resting heart rate:Prognostic importance of resting heart rate:epidemiological evidence epidemiological evidence (in general population and hypertensives)(in general population and hypertensives)

During 25 years - more than 155 000 patients, follow-up 8-36 years

Adapted from V. Aboyans et al., J Clin Epidemiol. 2006;59:547-558.

Study Population Follow-up Cardiovascular mortality RR

Chicago Gas Company ’80 1 233 M 15 y >94 vs. ≤60 bpm 2.3

Chicago Heart Ass.Project ’80 33 781 M&W 22 y ≥90 vs. <70 bpm M: 1.6 W: 1.1 (ns)

Framingham ’93 4 530 M&W HTN 36 y >100 vs. <60 bpm M: 1.5 W: 1.4 (ns)

British Regional Heart ’93 735 M 8 y >90 vs. ≤ 90 bpm IHD death 3.3

Spandau ’97 4 756 M&W 12 y Sudden death 5.2 per 20 bpm

Benetos ’99 19 386 M&W 18.2 y >100 vs. <60 bpm M: 2.2 W: 1.1 (ns)

Castel ’99 1 938 M&W 12 y 5th vs. 3rd quintile M: 1.6 W: 1.1

Cordis ’00 3 257 M 8 y ≥90 vs. <70 bpm 2.0

Reunanen ’00 10 717 M&W 23 y M: 1.4 (>84 vs. <60) W: 1.5 (>94 vs.<66)

Thomas ’01 60 343 M HTN 14 y >80 vs. ≤ 80 bpm <55y:1.5 >55y:1.3

Matiss ’01 2 533 M 9 y per 20 bpm: 1.5 ≥90 vs. <60 bpm: 2.7

Ohasama ’04 1 780 M&W 10 y M: 1.2 W: 1.1 (ns) per 5 bpm

Okamura ’04 8 800 M&W 16.5 y per 11 bpm (1 SD) M: 1.3 W: 1.2

Jouven ’05 5 713 M 23 y Sudden death from AMI 3.92 (>75 bpm)

The Paris Prospective Study I , general population, 5713 men; 23-year follow-up

Sudden death risk increases progressively withSudden death risk increases progressively withresting HR in the general populationresting HR in the 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

Rel

ativ

e ri

sk

Resting heart rate (bpm)

<60 60-64 65-69 70-75 >75

P<0.001

Prognostic dimension of resting heart rate and its changes

The Paris Prospective Study I , general population, n=5139; > 20-year follow-up

Jouven X, et al. Am J Cardiol. 2009;103:279-283

Tertiles of baseline HR:Tertiles of baseline HR:- low (64 bpm) - low (64 bpm) - medium (64 to 70 bpm)- medium (64 to 70 bpm)- high (70 bpm) - high (70 bpm)

Tertiles of HR change:Tertiles of HR change:- tertile 1 - decrease 4 bpm- tertile 1 - decrease 4 bpm- tertile 2 - 4- 3 bpm- tertile 2 - 4- 3 bpm- tertile 3 - increase 3 bpm- tertile 3 - increase 3 bpm

Relative risk of total mortality according to baseline HR and HR change after 5 years (after adjustment)

The Framingham Study, 2037 men with untreated hypertension, 36-year follow-up

All-cause mortality increases progressivelyAll-cause mortality increases progressivelywith resting heart rate in men with hypertension with resting heart rate in men with hypertension

Gillman MW, et al., Am Heart J. 1993;125:1148-1154.

00

1010

2020

3030

4040

5050

6060

<65<65 65-7465-74 75-8475-84 >84

CHD: 95% CI 1.20, 2.71CHD: 95% CI 1.20, 2.71

CVD: 95% CI 1.19, 2.37CVD: 95% CI 1.19, 2.37

All-cause: 95% CI 1.68, 2.83All-cause: 95% CI 1.68, 2.83

Age

-adj

uste

d 2-

year

dea

th r

ate

per

1000

Age

-adj

uste

d 2-

year

dea

th r

ate

per

1000

Resting heart rate (bpm)Resting heart rate (bpm)


Association independent of other cardiovascular risk factorsAssociation independent of other cardiovascular risk factors




disease disease





French cohort study, n=19 386 (12 123 men, 7263 women), 18-year follow-up

Benetos A, et al., Hypertension.1999;33:44-52.

Men: all-cause mortality Women: all-cause mortality

Resting heart rate independently predicts totalResting heart rate independently predicts totaland CV mortality in men and womenand CV mortality in men and women

1.00

0.95

0.90

0.85

0.80

0.75

0.70

Survival probability

Follow-up (years)

1 3 5 7 9 11 13 15 17 19 21

P (Cox)=0.0001

1.00

0.95

0.90

0.85

0.80

0.75

0.70


Follow-up (years)

1 3 5 7 9 11 13 15 17 19 21

P (Cox)=0.0001

HR<60 60≤HR≤80 80<HR≤100 HR>100 bpm

Resting heart rate as an independent Resting heart rate as an independent predictor of coronary events in womenpredictor of coronary events in women

129 135 postmenopausal women, a mean of 7.8 years of follow-up

Hsia J et al. BMJ. 2009;338:b219Hsia J et al. BMJ. 2009;338:b219

Resting heart rate as an independent predictor of coronary events (myocardial infarction or coronary death) in multivariable analisys

Hazard ratio (95% CI) P value

Resting heart rate, bpm 0.001

< 62 (reference) 1.00

63 – 66 1.02 (0.89 to 1.17))

67-70 1.08 (0.95 to 1.23)

71-76 1.02 (0.89 to 1.16)

> 76 1.26 (1.11 to 1.42)

Cohort study in 1407 men aged from 65 to 70 years, follow-up 18 years

Resting heart rate:Resting heart rate:predicts survival in people aged >65 yearspredicts survival in people aged >65 years

Benetos A et al., J Am Geriatr Soc. 2003;51:284-285.

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2<60 60-80 >80


Resting heart rate independently predictsResting heart rate independently predictsmortality in Western and Asian populationsmortality in Western and Asian populations

Okamura T et al., Am Heart J. 2004;147:1024-1032. Benetos A et al., Hypertension.1999;33:44-52.

HR<60 60≤HR≤80 80<HR≤100 HR>100 bpm

Survival probability curves for CVmortality in French men (n=12 123)

7 10 15 21Follow-up (years)

1.00

0.95

0.85

0.80

1 17 1913131353

0.90

P (Cox)=0.0001


Cumulative survival rates due to cardiacevents in Japanese men (n=3856)

Q1

Q2Q3

Q4

<60 bpm

60-65 bpm66-73 bpm

78 bpm

1.00

0.99

0.98

0.97

Cum

ula

tive

sur

viva

l rat

e

0 5 10 15 20Person-years

1.00

0.99

0.98

0.97

0






disease disease





1807 patients within 24 h of onset of symptoms of acute myocardial infarction

Mortality versus admission heart rate Mortality versus admission heart rate with acute myocardial infarction with acute myocardial infarction

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

0

10

20

30

40

50

Mor

talit

y (%

)

<50 50-59 60-69 70-79 80-89 90-99 100-109 110-119 120

Total

In-hospital

Post-discharge


Heart rate at admission and in-hospital mortality in MI survivors

Zuanetti G, et al. Eur Heart J. 1999;1 (suppl. H):H52-H57.

GISSI-3 study, 6-month follow-up; ECG

Heart rate (bpm)

n=2364 n=5305 n=2785 n=713

10.1

6.3

3.53.3

In-h

ospi

tal m

orta

lity

(%)

0

2

4

6

8

10

12

<60 60-80 81-100 >100

Heart rate at discharge and 6-month mortalityin MI survivors

Zuanetti G, et al. Eur Heart J. 1999;1 (suppl. H):H52-H57.

20.2

9.3

3.91.9

Heart rate (bpm)

n=4038 n=5600 n=1278 n=114<60 60-80 81-100 >100

6-m

onth

mor

talit

y (%

)

0

5

10

15

20

25

GISSI-3 study, 6-month follow-up; ECG

A high resting heart rate as an independentA high resting heart rate as an independentpredictor of mortality in CAD patientspredictor of mortality in CAD patients

The Coronary Artery Surgery Study (CASS) registry; 24 913 CAD patients; 14.1-year follow-up

Diaz A, et al. Eur Heart J. 2005;26:867-874.

Years after enrolmentYears after enrolment

Adjusted survival curves foroverall mortality

Adjusted survival curvesfor cardiovascular mortality

Cum

ula

tive

sur

viva

l

P<0.0001

0 5 10 15 20

0.5

0.6

0.7

0.8

0.9

1.0

P<0.0001

0 5 10 15 20

0.5

0.6

0.7

0.8

0.9

1.0

≤62 63-70 71-76 77-82 ≥83 bpm

Kolloch et al., Eur Heart J. 2008;29:1327-34.

INVEST study, 22 192 CAD patients; 2.7-year follow-up

Impact of heart rate in patients with Impact of heart rate in patients with hypertension and coronary artery diseasehypertension and coronary artery disease

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

> 10

0

Adv

erse

ou

tcom

e

inci

denc

e (%

)E

stima

ted hazard

ratio

Resting heart rate as a predictor of prognosisResting heart rate as a predictor of prognosis in patients with stable CAD in patients with stable CAD

JE. Ho et al. Presented at ACC 2009JE. Ho et al. Presented at ACC 2009

Post hoc analysis in 9580 patients from the TNT study, median follow-up was 4.9 years

JE. Ho et al. Presented at ACC 2009

Heart rate as a predictor ofHeart rate as a predictor ofcardiovascular deathcardiovascular death

% with cardiovascular death

Heart rate < 70 bpm

Heart rate ≥ 70 bpmP = 0.0041

Hazard ratio = 1.34 (1.10 – 1.63)

Years0 0.5 1 1.5 2

0

5

10

15

Fox K, et al. Lancet. 2008;372:817-821

Prospective data from the BEAUTIFUL placebo arm; 5438 patients with stable CAD and LVSD

Heart rate as a predictor ofHeart rate as a predictor ofhospitalization for heart failurehospitalization for heart failure

% with hospitalization for heart failure

0

5

10

15

Years0 0.5 1 1.5 2

P < 0.0001

Hazard ratio = 1.53 (1.25 – 1.88)

Heart rate < 70 bpm

Heart rate ≥ 70 bpm

Fox K, et al. Lancet. 2008;372:817-821


Heart rate as a predictor of Heart rate as a predictor of hospitalization for myocardial infarctionhospitalization for myocardial infarction

P = 0.0066

Hazard ratio = 1.46 (1.11 – 1.91)

Years

0 0.5 1 1.5 2

0

Heart rate < 70 bpm

Heart rate ≥ 70 bpm

8

% with hospitalization for fatal and nonfatal MI

0

4

6

2

Fox K, et al. Lancet. 2008;372:817-821







disease disease





Elevated Heart RateElevated Heart RateElevated Heart RateElevated Heart Rate

IschemiaIschemia Major CV eventsMajor CV events

Increased OIncreased O22 demand demand

Decreased supplyDecreased supplyIncreased OIncreased O22 demand demand

Decreased supplyDecreased supplyProgression of Progression of atherosclerosisatherosclerosisProgression of Progression of atherosclerosisatherosclerosis

PlaquePlaquerupturerupturePlaquePlaquerupturerupture

Short termShort term Long termLong term


Vascular damageVascular damageVascular damageVascular damage

Role of elevated HR in the pathophysiology of CADRole of elevated HR in the pathophysiology of CAD

HR as a trigger of ischemia in stable angina patientsHR as a trigger of ischemia in stable angina patients

Kop W et al. J Am Coll Cardiol. 2001;38:742.

STdepressionSTdepression

100100

9595

9090

8585

8080

7575

7070

60 20 10 4 260 20 10 4 2 2 10 20 602 10 20 60EventEvent

Time (min)Time (min)

**

********

****

**** ****

100100

9595

9090

8585

8080

7575

7070

60 20 10 4 260 20 10 4 2 2 10 20 602 10 20 60EventEvent

**

********

****

**** ****

Angina Angina

100100

9595

9090

8585

8080

7575

7070

656560 20 10 4 260 20 10 4 2 2 10 20 602 10 20 60EventEvent

**

********

****

**** ****

Hea

rt r

ate

, b

pm

n=19 men with stable CAD; 48-AECGn=19 men with stable CAD; 48-AECG

* P <0.05** P <0.01

Heart rate as a major determinant of ischemiaHeart rate as a major determinant of ischemia

Andrews TC et al. Circulation.1993;88:90-100.

00

44

88

1212

1616

2020

Likelihood of ischemia, %Likelihood of ischemia, %

<60<60 60-6960-69 70-79 80-89 70-79 80-89 >89>89

Heart rate at rest, bpmHeart rate at rest, bpm

x2x2

n=50 stable CAD patients; 48-AECG

Heart rate as predictor of ischemic episodes: Heart rate as predictor of ischemic episodes: multivariate analysismultivariate analysis

Multivariate analysis of variables predictive of an ischemic episode Multivariate analysis of variables predictive of an ischemic episode after a period of HR increaseafter a period of HR increase


Magnitude of heart rate increaseMagnitude of heart rate increase -0.56-0.56 0.00010.0001

Baseline heart rateBaseline heart rate -0.45-0.45 0.00010.0001

Duration of heart rate increaseDuration of heart rate increase -0.04-0.04 0.050.05

Standardized estimateStandardized estimate PP

Andrews TC et al. Circulation.1993;88:90-100.


HR as a predictor of coronary eventsHR as a predictor of coronary events

Aronov W. S et al. Am J Cardiol. 1996;78:1175-1176.

New

co

ron

ary

eve

nts

, %

N

ew c

oro

nar

y ev

en

ts,

%

<60<60 61-7061-70 71-8071-80 81-9081-90 91-10091-100 >100>10000

1010

2020

3030

4040

5050

6060

7070

Mean heart rateMean heart rate

n=1311 older CHD patients; 48-month follow-up; 24-h AECGn=1311 older CHD patients; 48-month follow-up; 24-h AECG

P<0.0001

5 bpm of HR = 1.14 incidence of coronary events5 bpm of HR = 1.14 incidence of coronary events

Perski A, et al. Am Heart J. 1988;116:1369-1373.

Heart rate and coronary atherosclerosisHeart rate and coronary atherosclerosis

Minimum heart rate (bpm)

Cor

onar

y a

t her

oscl

eros

is s

core

(%

)

50

0

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

Heart rate and coronary plaque ruptureHeart rate and coronary plaque rupture

Multivariate analysis of association with coronary plaque disruption

Left ventricular mass >270 g 4.92 (1.83-13.25) 0.02

Mean heart rate >80 bpm 3.19 (1.15-8.85) 0.02

-Blocker use 0.32 (0.13-0.88) 0.02

Wall thickness IVS 1.68 (0.57-9.91) 0.06

Fractional pulse pressure 1.81 (0.67-4.90) 0.07

Statins 0.42 (0.16-1.22) 0.06

OR (95% CI) P

ACE inhibitors 0.51 (0.19-1.34) 0.06

106 patients with 2 coronary angiographies; 6-month follow-up; 24-h EGG

Heidland UE, Strauer BE. Circulation. 2001;104:1477-1482.

Variation of coronary flow and shear stressVariation of coronary flow and shear stressduring the cardiac cycleduring the cardiac cycle

10 mm Hg DIASTOLEDIASTOLE120 mm Hg

Adapted from Giannoglou G et al. Int J Cardiol. 2008;126:302-312

SYSTOLESYSTOLE

No flow No flow (even (even retrograde subendocardialretrograde subendocardial flow)flow)

No flow No flow (even (even retrograde subendocardialretrograde subendocardial flow)flow)

Coronary arterial flow Coronary arterial flow (myocardial perfusion)(myocardial perfusion)

Coronary arterial flow Coronary arterial flow (myocardial perfusion)(myocardial perfusion)

Increased shear stressIncreased shear stressIncreased shear stressIncreased shear stressLow and oscillatory shear stressLow and oscillatory shear stressLow and oscillatory shear stressLow and oscillatory shear stress

Coronary arteries are prone to atherosclerosisCoronary arteries are prone to atherosclerosis

Heart rate and atherosclerosis: potential mechanisms

Adapted from Giannoglou G et al. Int J Cardiol. 2008;126:302-312


Endothelial damageEndothelial damageEndothelial damageEndothelial damage

Elevated heart rateElevated heart rate

Shift of endothelial cells to Shift of endothelial cells to an atherosclerotic an atherosclerotic

phenotypephenotype

Shift of endothelial cells to Shift of endothelial cells to an atherosclerotic an atherosclerotic

phenotypephenotype

Plaque rupturePlaque rupture

Mechanical arterial Mechanical arterial wall stresswall stress

Shortening of Shortening of diastolic perioddiastolic period

Wall damageWall damageWall damageWall damage

Shortening of coronary Shortening of coronary perfusion timeperfusion time

Shortening of coronary Shortening of coronary perfusion timeperfusion time

Long-term consequences of a low shear stress for the Long-term consequences of a low shear stress for the coronary arterial wallcoronary arterial wall

Atherosclerotic plaque formation/progression and vascular remodelingAtherosclerotic plaque formation/progression and vascular remodelingAtherosclerotic plaque formation/progression and vascular remodelingAtherosclerotic plaque formation/progression and vascular remodeling

Adapted from Chatzizisis YS et al. Adapted from Chatzizisis YS et al. J Am Coll Cardiol.J Am Coll Cardiol. 2007;49:2379–2393 2007;49:2379–2393

ROSROS LDL uptake andLDL uptake andsynthesissynthesis

VCAM-1, ICAM-1VCAM-1, ICAM-1E-selectinE-selectin

TNF– TNF– IL-1, IFN-IL-1, IFN-

Growth Growth promoterspromoters

Growth Growth inhibitors,inhibitors,

eg, TGF-eg, TGF-, NO, NO

Apoptosis and Apoptosis and proliferationproliferation

ROSROS

NONO

eNOSeNOS

Impaired NO-Impaired NO-dependent dependent

atheroprotectionatheroprotection

ThrombogenicityThrombogenicity

oxLDLoxLDL Matrix degradationMatrix degradation InflammationInflammation AngiogenesisAngiogenesis Matrix Matrix synthesissynthesis

NAPDHNAPDHoxidaseoxidase

Low shear stressLow shear stress

Inner curvature:

low ESS region (artherosclerosis-prone)

Early fibroatheroma

Constricitve remodeling

Stenotic plaque

Stable angina

Compensatory expansive remodeling

Quiescent plaque

AsymptomaticAcute coronary

syndrome

Erosion

Microruptures

Rup

ture

Excessive expansive remodeling

Thin cap fibroatheroma

• Local factors, eg, low ESSLocal factors, eg, low ESS

• Systemic factors, eg, hyperlipidemiaSystemic factors, eg, hyperlipidemia

• Genetic factorsGenetic factorsLow ESS

Physiologic ESS

Limited inflammation High ESS

Lower ESS

Vulnerability

Intense inflammmation

Fibroproliferation

Natural history of coronary atherosclerosisNatural history of coronary atherosclerosis

Adapted from Chatzizisis YS et al. Adapted from Chatzizisis YS et al. J Am Coll Cardiol.J Am Coll Cardiol. 2007;49:2379-93) 2007;49:2379-93)

Increases the mechanical load on the arterial wallIncreases the mechanical load on the arterial wall

Induces structural and functional changes of the endothelialInduces structural and functional changes of the endothelial

cells making intima more permeable to circulating LDL andcells making intima more permeable to circulating LDL and

inflammatory cellsinflammatory cells

Promotes the weakening of the fibrous cap, leading to plaquePromotes the weakening of the fibrous cap, leading to plaque

disruption and the onset of acute coronary syndrome disruption and the onset of acute coronary syndrome

Putative mechanisms underlyingPutative mechanisms underlyingpro-atherosclerotic effect of increasing heart ratepro-atherosclerotic effect of increasing heart rate






disease disease





Heart rate reduction with Ivabradine prevents endothelial Heart rate reduction with Ivabradine prevents endothelial dysfunction associated with dyslipidemia in micedysfunction associated with dyslipidemia in mice

Drouin et al. Br J Pharmacol. 2008;154:749-757

Metoprolol does not prevent cerebral endothelial dysfunction associated with dyslipidemiaMetoprolol does not prevent cerebral endothelial dysfunction associated with dyslipidemia

CC DD

AA BB

Reduction in atherogenesis with ivabradineReduction in atherogenesis with ivabradine

Böhm M et al. Circulation. 2008;117:2377-2387

Ascending aorta *P<0.05

Apolipoprotein E–deficient mouse model

Aortic sinus

IvabradineVehicle

40

30

20

10

0

Pla

que

are

a[%

to

tal]

*

30

20

10

0

Pla

que

are

a[%

tota

l]

Vehicle Ivabradine

40%

70%

Ivabradine reduces fatal and nonfatal Ivabradine reduces fatal and nonfatal myocardial infarction (HR ≥70 bpm)myocardial infarction (HR ≥70 bpm)

Ho

spit

aliz

atio

n f

or

fata

l o

r n

on

fata

l M

I %

Placebo(HR >70 bpm)

Ivabradine Ivabradine

P = 0.001

Hazard ratio = 0.64 (0.49 – 0.84)

years

0 0.5 1 1.5 2

0

4

8

RRR 36%

RRR: relative risk reduction

Fox K, et al. Lancet. 2008;372:807-816

years

0 0.5 1 1.5 2

0

4

Ivabradine Ivabradine

8

Co

ron

ary

reva

scu

l ari

zati

on

% P = 0.016

Hazard ratio = 0.70 (0.52 – 0.93)

RRR 30%

Fox K, et al. Lancet. 2008;372:807-816

Placebo

Ivabradine reduces the need for Ivabradine reduces the need for revascularization (HR ≥70 bpm)revascularization (HR ≥70 bpm)


0.1140.11431%31%0.690.69Fatal MIFatal MI

0.0230.02322%22%0.780.78Fatal and nonfatal MI or unstable anginaFatal and nonfatal MI or unstable angina

0.0160.01630%30%0.700.70Coronary revascularizationCoronary revascularization

0.0090.00923%23%0.770.77Fatal and nonfatal MI, unstable anginaFatal and nonfatal MI, unstable anginaor revascularizationor revascularization

0.0010.00136%36%0.640.64Fatal and nonfatal MIFatal and nonfatal MI

P valueP valueRiskRiskreductionreduction

HazardHazardratioratio

Predefined end pointPredefined end point

Ivabradine reduces coronary risk inIvabradine reduces coronary risk instable coronary patients with HR ≥ 70 bpmstable coronary patients with HR ≥ 70 bpm

Fox K, et al. Lancet. 2008;372:807-816

years

Ho

spit

aliz

atio

n f

or

fata

l o

r n

on

fata

l M

I %

Fox K, et al. Lancet. 2008;372:807-816

Placebo(HR >70 bpm)

Ivabradine(HR baseline > 70 bpm)

Ivabradine(HR baseline > 70 bpm)

P = 0.001

Hazard ratio = 0.64 (0.49 – 0.84)

0 0.5 1 1.5 2

0

4

8

RRR 36%Placebo

(HR <70 bpm)

Ivabradine shifts the patients Ivabradine shifts the patients from high risk to low riskfrom high risk to low risk


ConclusionsConclusions

Heart rate is a risk factor for cardiovascular mortality, independent of major conventional risk factors

Heart rate should be used to assess cardiovascular risk and to guide medical therapy of patients with coronary disease

BEAUTIFUL data suggest benefit from heart rate reduction with Ivabradine in patients with coronary artery disease and heart rate above 70 bpm

the pivotal role of heart rate in cardiovascular disease

Documents

increased heart rate

coronary risk

heart rate reduction

increasing heart rate

coronary heart disease

elevated admission heart

cardiovascular risk

stable coronary patients