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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