Management of the

coronary patient

in 2011

Roberto Ferrari

In the era of interventional cardiology, is chronic

stable angina a “rare disease”?

What is new in treatment

of stable CAD?

Stable angina pectoris

Prevalence in EuropePrevalence in community studies

(Rose questionnaire)

Age (yrs) Males Females

45-54 2-5% 0.1-1%

65-74 10-20% 10-15%

20.000-40.000 individuals per million population (2-4%)

ESC Guidelines Eur Heart J 2006

Stable angina pectoris

Incidence in Europe

Annual incidence ~0.5% in

Western populations, with

large geographic variations

(twice as high in Scotland

compared to France)

ESC Guidelines Eur Heart J 2006

Shift in stable CAD

epidemiology

• Decline incidence in younger

• Increased incidence in elderly

• Prevalence expected to increase

• Despite interventional cardiology stable CAD

remains a public health

problem

• 2.6% of total health expenditure

in the EU (45.000.000 €)

Pharmacological treatment of

stable angina

• Anti-anginal (improves symptoms/exercise

capacity, quality of life)

• Cardioprotective (prevention of cardiovascular

outcomes)

Outcome improvement

• Anti-platelet agents•Aspirin •Clopidogrel (if aspirin not tolerated)

• Lipid-lowering drugs• Statins

• ACE-inhibitors •Ramipril and perindopril

• β-blockers•Only in post MI and HF patients

Ivabradine

•Inhibits the If current of the sinus node cells

•Is a prototype of a new class of drugs and the first and

only pure HR reducing agent

mV

pA

500

-50

-50

ICaL

50

IK

ms0

-50

INaCa

-50

ICaT

-50

If

Sinus node action potential and currents

Ca channel

T- type

Ca channel

L- type

K channel

f-channel

Sinus node

Robinson RB, DiFrancesco D. Fundamental and Clinical Cardiology; NY; Marcel Decker; 2001:151-170.

Sinus node channels

If current in the sinus node:

the determinant of HR

Suppression of If CurrentRR

0 mV

-40 mV

-70 mV

• 30% reduction of diastolic slope• other currents maintain pacemaker activity• safety factor of ivabradine

Heart ratereduction

exclusively

Ivabradine

Extracellular

side

Closed Open Inihibited

Na+ K+ Ivabradine

Intracellular

side

Bucchi A, Baruscotti M, DiFrancesco D. J Gen Physiol. 2002;120:1-13

When the channel is in closed state

(bradycardia) ivabradine is inactive.

Ivabradine interacts internaly with

the If channel: a safety valve

HR dependent effect of ivabradine

Camm J et al. JACC. 2007;49 (Suppl1).Abstract.

The higher the rate, the higher the penetration,

the greater the effect and vice versa

HR: the determinant of ischaemia

60 20 10 4 2 2 10 20 60

Time (min)

100

95

90

85

80

75

70

65

**

**

*

**

**

**

Change in HR one hour surrounding an

ischaemic eventAdapted from Kop WJ et al J. Am Coll C Cardiol 2001;38:742-749

n = 19* p

Ivabradine and angina

On top of atenololAgainst amlodipine

Against placebo Against atenolol

54

56

58

60

62

64

66

68

Baseline M2 M4

Ivabradine

5 mg bid

Ivabradine 7.5 mg bid (90% of pts) or 5 mg bid (10%)

67

60 (-7 bpm)

58 (-9 bpm)

Ivabradine +

atenolol

atenolol

Placebo +

889 stable angina patients, 20 countries

Tardif JC et al. Eur Heart J. 2008;29:386

Effects on HR in patients

already receiving β-blockers

Anti-ischaemic efficacy of ivabradine

in combination with -blockers

Ivabradine on top of usual dose of β-blockers improves

all parameters of exercise capacity without safety concerns

889 patients with stable angina, 4 months of treatment

Tardif JC et al. Eur Heart J. 2008;29:386 .

ivabradine + atenolol

placebo + atenolol

0

10

20

30

40

50

60

Time to 1mm ST

depression

P

Simon L et al. J Pharmacol Exp Ther. 275:659-666, 1995

Heart rate

* P

8Change from

baseline (%)

Simon L, et al. J Pharmacol Exp Ther. 1995;275:659-666.

*

*

++

++

+

++ ++

++

Baseline Exercise 5 min 10 min 12 min

6

4

2

0

-2

-4

-6

-8

Saline

0.5 mg/kg Ivabradine

1.0 mg/kg Propranolol

* p

NORADRENALINE

β

Coronary

dilatation

Coronary

constriction

α

0

2

4

6

8

10

12

Atenolol 100 mg

Increase in TED related to 1 beat of heart rate reduction(after 4-month treatment)

5.6

10.1

Tardif JC, et al. Eur Heart J. 2005;26:2529-2536.

Ivabradine 7.5mg

Intrinsic more efficiency

of Ivabradine vs atenolol

Ivabradine allows coronary dilatation

x

x

Bradycardia

Hypotension

Negative inotropic effect

Peripheral vasoconstriction

Increase coronary resistance

Bronchospasm

Decrease to insuline response

Fatigue

Depression

Sleep disturbancies

Erectile dysfunction

Lower limbs oedema

Constipation

Visual effects

x

x

x

x

x

x

x

x

x

x

x

x

+/-

x

x

x

x

x

x

BB CCB Ivabradine

Pure HR reduction with Ivabradine does not

cause the side-effects of the -blockers and calcium-channel-blockers

New EMEA indications

"Symptomatic treatment of chronic stable angina pectoris in coronary artery disease patients with normal sinus rhythm. Ivabradine is indicated :

• in patients unable to tolerate or with a contra-indication to the use of -blockers

• or in combination with -blockers in patients inadequately controlled with an optimal -blocker dose and whose heart rate is > 60 bpm."

Ivabradine programme

•Symptoms release in angina (12.000 P)

•Prognostic improvement in CAD with or without LV dysfunction

(BEAUTifUL and SIGNifY 24.000 P)

•Prognostic improvement in HF (SHifT 6.500 P)

HR as a predictor of

CARDIOVASCULAR DEATH HOSPITALISATION FOR HF

HOSPITALISATION FOR MI REVASCULARISATION

Effect of ivabradine on the primary

endpoint (overall population)

Effect of ivabradine on the primary

composite endpoint (HR ≥ 70 bpm)

Effect of ivabradine on

hospitalisation for MI (HR ≥ 70 bpm)

Effect of ivabradine on coronary

revascularisation (HR ≥ 70 bpm)

Effect of ivabradine on 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 0.5 1 1.5 2

Eve

nt ra

te (

%)

0

5

10

15

20

25

30

0 0.5 1 1.5 2

Eve

nt ra

te (

%)

All angina patients HR >70 bpm

24% 31%Placebo

Ivabradine

Placebo

Ivabradine

* Composite of cardiovascular mortality or hospitalization for fatal and

nonfatal myocardial infarction or heart failure Fox et al. Eur Heart J. In press.

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 0.5 1 1.5 2

Even

t ra

te (

%)

0

5

10

15

0 0.5 1 1.5 2

Event ra

te (

%)

42% 73%

Effect of ivabradine on

hospitalisation for MI

All angina patients HR >70 bpm

* Fatal and nonfatal events Fox et al. Eur Heart J. In press.

Beta-blockers, % 8790 89

Statin, % 64 67 74

Antithrombotics, % 92 92 94

86Anti-RAS, % 88 90

Treatment

75Organic Nitrates, % 72 43

PlaceboAngina Substudy

n=773

IvabradineAngina Substudy

n=734

BEAUTifULAll

n=10 917

Ivabradine - The first anti-anginal agent with demonstrated reduction of MI

in stable CAD

Adapted from: Guidelines on the management of stable angina pectoris. Eur Heart J. 2006;27:1341-1381.

Fox K et al. Lancet Online August 31, 2008.

Ranolazine

Trimetazidine

-Blockers

Calcium antag.

Nitrates

Nicorandil

Ivabradine

Improved

time to onset

of ST segment

depression

+

+

+

+

+

+

+

Decrease

in anginal

episodes

+

+

+

+

+

+

+

Improved

total

exercise

duration

+

+

+

+

+

+

+

Reduced

revascularisation

NA

NA

–

+

–

NA

+

Prevention

of MI

NA

NA

–

–

–

–

+

Improved

survival

NA

NA

–

–

–

–

+

FROM

TO

Why?

HR and the CV system

• HR is a determinant of the energy needs of the heart

• HR controls energy deliveryto the heart

• High HR impairs endothelial function and facilitates

atherosclerosis

• 93 600 beats• 13.5 millions of billions of Ca2+ mobilised• almost 30 kg ATP immediately used• 9000 lt blood ejected!• 132.000 km in 27 seconds!

but … in a day?

HR and the heart: its costFor each beat• 1.35x10-19 Ca2+ ions mobilised• 300 mg ATP used for contraction• 89 ml blood ejected

HR and the heart: a reduction of

10 bpm/day saves 5 kg ATP

Essential to maintain vitality

HR and the coronary arteriesC

oro

nary

flo

wSYSTOLE DIASTOLE

Coronary flow occurs mainly in diastole

http://www.cardiovascularultrasound.com/content/3/1/8/figure/F1?highres=y

HR and atherosclerosis:

plaque development

Diameter stenosis (%)Atherosclerotic cross-

sectional area (mm2)

Heart rate

Sinoatrial

node

ablation

Beere et al. Science. 1984;226:180-2.

136

(22)

103

(20)

Bradycardia reduces progression of atherosclerosis

HR and atherosclerosis

HR reduction by ivabradine delays atherosclerosis

in apolipoprotein E deficient mice

Cu

sto

dis

et

al.

Cir

c. 2

00

8:1

17

.

Heidland and Strauer. Circulation. 2001;104:1477-81.

HR and coronary plaque rupture

Bradycardia prevents acute coronary syndromes

Ivabradine: consideration

• Well defined mechanism of action

• HR of anginal patients must be reduced to 60 bpm

• Ivabradine alone or on top of ß-blockers improves symptoms

of angina

REDUCTION: Reduction of ischaemic Events by reDUCtion of hearT rate In the treatment Of stable

aNgina with Procoralan

Multicenter, prospective, open label, study (Germany); 4,954 angina pts; 4 months follow up

60

70

80

90

100

Baseline 1 month 4 months

Starting

dose: 9.0 mg bid

(80.3% - 5 mg bid)

Average

dose: 10.2 mg bid

(14% - 7.5 mg bid)

Averag

e dose: 10.5 mg bid

(19% - 7.5 mg bid)

Koster R, Kaehler J, Meinertz T, for the REDUCTION Study Group. Am Heart J 2009;158:e51-e57

Cardiovascular therapy

before Procoralan

ASS 82%

Statin 66%

ACEI 53%

ARA 19%

β-blocker 54%*

LA nitrates 25%

CCB 25%

* During the Procoralan therapy, 6.9%

patients were treated concomitantly using

a B-blocker.

REDUCTION: proof of anti-anginal efficacy of Procoralan under routine practice conditions

Angina attacks

0.4

0

2

3

1

Baseline After 4 months

- 80 %

0

2

4

3

1

Baseline After 4 months

- 82%

3.32.4

Efficacy was graded by physicians as being “excellent/very good” for 97% of the patients

Acute nitrate consumption

Koster R, Kaehler J, Meinertz T, for the REDUCTION Study Group. Am Heart J 2009;158:e51-e57

0.6P

Study objective

To assess the efficacy of

ivabradine vs placebo in

prevention of CV events in

patients with stable CAD

without clinical HF

• Outpatients with stable CAD• Age > 55 years • With at least one other CV

risk factor

• Without LVSD (LVEF > 40%) or clinical signs of HF

Population

• With resting HR>70 bpm (two consecutive ECG recordings at

5 min apart, at selection and

inclusion visits) and in sinus

rhythm

• Receiving appropriate guide-lines driven CV medication

Population

Ivabradine programme

•Symptoms release in angina (12.000 P)

•Prognostic improvement in CAD with or without LV dysfunction

(BEAUTifUL and SIGNifY 24.000 P)

•Prognostic improvement in HF (SHifT, 6.500 P)

Angina Rationale

• Angina is preceded by HR

• HR reduction by Ivabradine

- reduces O2 demand

- improves O2 delivery