Capri Cardiovascular Conference 2.0
Il ruolo dell‘ ivabradina nella gestione terapeutica
delle malattie cardiovascolari oggi
LINEE GUIDA PER IL TRATTAMENTO DELLA CARDIOPATIA ISCHEMICA
Andrea Macchi
U.O.C. di Cardiologia, UTIC ed Emodinamica
A.O. Ospedale di Circolo di Busto Arsizio (VA)
Capri (Na), 28-29 Marzo 2014
HR AS A PREDICTOR OF CV DEATH, ADMISSION FOR HF,
MI AND CORONARY REVASC IN PTS WITH CAD AND
LVSD
RESTING HEART RATE INDEPENDENT
PREDICTOR OF MORTALITY IN CAD
The Coronary Artery Surgery Study (CASS) registry 24. 913 CAD
patients; 14.1-year follow-up
Obiettivo fisiopatologico
placebo arm (n=5438)
Adjusted survival curves
for cardiovascular mortality
Adjusted survival curves for
overall mortality
CV death
Admission for HF
Cumulative survival
+34%
1.0
1.0
0.9
0.9
0.8
+53%
0.8
P<0.0001
P<0.0001
0.7
0.7
0.6
0.6
0.5
Coronary
revascularization
Admission for MI
+46%
+38%
0.5
0
5
10
≤62
15
20
5
0
Years after enrolment
63-70
71-76
77-82
10
15
20
1° studio prospettico
≥83 bpm
Fox K et al, Lancet 2008
Diaz A, et al. Eur Heart J. 2005;26:967-974
o
FC>70 bpm rischio CV aumentato
cut-off 70 bpm anche in OMT
Determinante del
consumo di
ossigeno miocardico
6.004 pts
HEART RATE AND CORONARY PLAQUE RUPTURE
Retrospective angiographic study 53 pts (out of 106)
Heidland UE, Strauer BE. Circulation. 2001
o
OR (95% CI)
P
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
ACE inhibitors
0.51 (0.19-1.34)
0.06
Statins
0.42 (0.16-1.22)
0.06
RIDURRE FC RIDUCE SINTOMI , ISCHEMIA ED EVENTI
•
Heart rate is a major determinant of myocardial oxigen demand and development
of ischaemia
•
Elevated heart rate is a risk factor of cardiovascular outcomes, independent of major
conventional risk factors
•
Heart rate should be used in risk stratifications and to guide optimal medical therapy
in patients with coronary disease or heart failure
…and heart rate lowering reduce cardiac ischaemia and has
a potential to improve the prognosis…
Effects on total exercise duration
Effects on time to 1 mm ST segment depression
The increase in time to 1 mm ST-segment depression by 1.5 min indicates that the
improvement in total exercise capacity is associated with a relevant anti-ischemic
effect
Tardif JC et al, Eur Heart J 2005
IVA vs -B
Iva increases exercise capacity to a greater extent for every beat of heart rate reduction
INITIATIVE Study
Riduzione FC con -B associata ad inotropismo negativo e smascheramento
della vasocostrizione coronarica a-adrenergica
Tardif JC et al, Eur Heart J 2005
ANTI-ISCHEMIC AND ANTIANGINAL EFFICACY OF
IVABRADINE VS AMLODIPINE
Amlodipine 10
(n=404) better
Ivabradine 7.5 (n=400)
better
P value
P<0.001
Total exercise duration
P<0.001
Time to limiting angina
Time to angina onset
P<0.001
Time to 1-mm ST-depression
P<0.001
- 30 sec
0
+30 sec
Ruzyllo W, et al. Drugs. 2007;67:393-405.
Ivabradina , bloccante selettivo dei canali if, riducendo FC:
•
•
diminuisce i marker dello stress ossidativo vascolare, migliora la
funzione endoteliale e riduce la formazione della placca aterosclerotica
riduce il rischio di eventi coronarici del 22% (p=0.023), il rischio di IMA
fatale e non fatale del 36% (p=0.001) e le rivascolazzazioni coronariche
del 30% (p=0.016) nei pazienti con FC basale > 70 bpm
Druin A et al ,Br J Pharmacol 2008
Custodis F et al, Circulation 2008
Tardif JC, Br Med Bull 2009
Angina limitante
IVA:
nei
pazienti
sintomatici
riduce l’incidenza di morte
CV, IMA, scompenso (-24%)
ed ospedalizzazione per
IMA fatale e non (-42%),
indipendentemente da FC
basale
K Fox et al, Eur Heart J 2009
Safety
In pazienti con coronaropatia e ventricolo sinistro disfunzionante IVA puo’
essere somministrata in piena sicurezza anche con il beta-bloccante
Fox K et al, Lancet 2008
PREVENZIONE SECONDARIA DELL’IMA
Numero di pazienti da trattare per prevenire un evento per anno (NNT-1)
Studio
Eventi
NNT-1
4S
Eventi coronarici
maggiori
63 pz
SAVE
IMA fatale e non
105 pz
bloccanti
Meta-analisi b
post-IMA
IMA non fatale
107 pz
Ivabradina
BEAUTIFUL
IMA fatale e non
93 pz
Statine
ACE-I
Tardif JC et al, Eur Heart J 2009
SAFETY OF IVABRADINE IN COMBINATION
WITH BETA-BLOCKER
Ivabradine Placebo
Bradycardia
Asymptomatic
3.0%
0.5%
Symptomatic
1.1%
0.3%
Withdrawal due to sinus bradycardia
0.9%
0%
Kjekshus J et al, Am J Cardiol 1995
Pfeffer MA et al, N Engl J Med 1992
Freemantle N et al, B Med J 1999
Fox K et al, Lancet 2008
ANGINA ATTACKS, S-A NITRATE CONSUMPTION, HR
2,425 pts from 5 IVA randomized trial
IVA reduced: angina attacks by 59.4%, nitrate consumption by 53.7%
IVA had a good safety and tolerability profile in all the subpopulations assessed
CHANGE IN HEART RATE (%)
5
-5
-15
-25
-35
-45
-55
2.330 pts
PVD
COPD
DIABETES
PREVIOUS CABG
CVD
PREVIOUS PCI
CCS III
PREVIOUS MI
CCS I
CCS II
AGE>75
WOMEN
-75
AGE>65
Tendera et al, Cardiology 2009
OVERALL
PVD
COPD
DIABETES
PREVIOUS CABG
CVD
PREVIOUS PCI
CCS III
PREVIOUS MI
CCS I
CCS II
AGE>75
WOMEN
AGE>65
-65
OVERALL
0
-2
-4
-6
-8
-10
-12
-14
-16
-18
CHANGE IN ANGINA ATTACKS (%)
HEART RATE REDUCTION DURING EXERCISE-INDUCED MYOCARDIAL ISCHAEMIA
AND STUNNING
o IVA
 Saline
 
IVA prima dell’ischemia riduce la disfunzione contrattile regionale, riduce significativamente la severita’ dello
stunning miocardico durante il recupero, aumentando il tempo di perfusione diastolica e la perfusione
subendocardica Tale effetto e’ abolito dal pacing
Il -bloccante ha effetto su ischemia ma non sullo stunning per la sua azione inotropa negativa
Monnet X et al, Eur Heart J 2004
CIRCULATION OF BLOOD IN CORONARY ARTERIES
Coronary flow occurs only in diastole « An increase of 1% of diastolic time, increases blood flow by 2,6 to 6% in the
subendocardium » - The difference between coronary artery pressure and LVEDP drives subendocardial perfusion
HEART RATE REDUCTION AND ISCHEMIA
Beta-Blockers
Reduced
cardiac work
Increased
diastolic time
Ivabradine
Reduced
cardiac work
Increased
O2 supply
Coronary
dilation Preserved strength of
contraction / relaxation
Coronary blood flow
Coronary blood flow
Reduced
O2 demand
Increased
diastolic time
Additional benefits of ivabradine
Reducing
O2 demand
Maximized
O2 supply
Better ventricular filling and
stress cardiac adaptation
“BEYOND HR REDUCTION”
IVA vs -B
CONTRATTILITA’ DA SFORZO
GITTATA CARDIACA DA SFORZO
DURATA DELLA DIASTOLE
RILASCIAMENTO VS
VASODILATAZIONE DA SFORZO
FLUSSO CORONARICO DA SFORZO
Simon L et al, J Pharmacol Exp Ther 1995
Colin P et al, Am J Physiol Heart Circ Physiol 2003
ADDITION OF IVABRADINE TO BISOPROLOL IMPROVES EXERCISE
CAPACITY MORE THAN UP-TITRATION OF BISOPROLOL
Work load on teadmill testing METs
7
р=0.004
6
5
4
Bisoprolol 5 mg
Bisoprolol 5 mg +
Ivabradine
Bisoprolol 5 mg
Bisoprolol 5 mg +
Bisoprolol 5 mg
Amosova et al J Am Coll Cardioal 2010
CHI TRATTIAMO ?
QUANDO INIZIAMO IL TRATTAMENTO ?
Non perdiamo una occasione
-BLOCKERS TREATED CAD PTS
IN THE REAL WORLD
HEART RATE IN CAD PTS RECEIVING
-BLOCKERS
Cohort studies
3
NO B
n. 1011
B
n. 1215
N = 2.226
Vitale C et al Ann Int Med 2010
HR DECREASE (AT REST) VS OTHER HR-LOWERING AGENTS
Ivabradine1
Diltiazem
0
180-240 mg bid2
200 - 300 mg od3
5 mg bid
n=208
n=182
n=595
7.5 mg bid
n=300
Atenolol1
50 mg od
100 mg od
n=286
-5
-10
-15
 (bpm)
1. Tardif JC, et al. Eur Heart J. 2005;26:2529-2539. 2. Wiegen HW, et al. J Cardiol Pharm. 1991;1b:S55-S60. 3. Pine MB. Circulation. 1982;65:17-22.
THE CLINICAL EXPERIENCE OF THE ITALIAN DRUG AGENCY
EFFECT OF IVABRADINE IN 14.256 PATIENTS WITH CORONARY ARTERY DISEASE
Source AIFA - Italian Drug Agency – Ivabradine Registry 2011
Baseline
Follow up
Heart Rate
83
69
Angina/week
GTN Use
3.3
1.7
0.67
0.3
Cardiac deaths
8
Discontinuation
136
Severe adverse reactions
Confirmed SARs
9
0
Hazard
ratio
Risk
reduction
P value
Fatal MI
0.69
31%
0.114
Fatal and nonfatal MI
0.64
36%
0.001
Fatal and nonfatal MI or unstable angina
0.78
22%
0.023
Fatal and nonfatal MI, unstable angina
or revascularization
0.77
23%
0.009
Coronary revascularization
0.70
30%
0.016
Predefined end point
IVABRADINE REDUCES
CORONARY RISK
IN
Angina
STABLE PATIENTS WITH
CAD AND HR ≥ 70 BPM
Fox K, et al. Lancet. 2008;372:807-816.
DRUGS AND PCI ON OUTCOMES IN STABLE CAD
Treatments
Studies in patients
with stable CAD
Findings
Dihydropyridine
CCBs
CAMELOT
ACTION
No impact on mortality or MI in CAMELOT
ACTION: no reduction in CV events
Nicorandil
IONA
Primary endpoint reduced, but no impact on mortality or non fatal MI
Ranolazione
MERLIN
No reduction of CV in subanalysis in angina pectoris
Beta-blockers
Meta regression analysis
CIBIS-II
Evidence only in post-MI and CHF
Others (nitrates,
diltiazem, verapamil)
No prognositic data in stable CAD patients
Prevention Improved
Reduced
of MI
survival
revascularization
-Blockers
–
–
+/–
+/-
–
–
Nitrates
–
–
–
Trimetazidine
+
+
+
Ranolazine
NA
–
–
Nicorandil
NA
–
–
Ivabradine
+
+
SHIFT
Calcium antagonists
Kereiakes DJ et al, J Am Coll Cardiol 2007
CLINICAL EFFECTS OF
ANTIANGINAL AGENTS
NA: not available, +: positive effect, -: no effect
Adapted from: Guidelines on the management of stable angina
pectoris. Eur Heart J. 2006;27:1341-1381. Fox K, et al. Lancet.
2008;372:807-816.
PLACE FOR IVABRADINE IN NEW GUIDELINES?
Clinical setting
Class
Level
Stable CAD with angina HR > 60
I
A
Chronic heart failure with reduced LVEF
I
B
EUROPEAN MEDICINE EVALUATION AGENCY INDICATION
Ivabradine is indicated as first line therapy alone or in combination with beta-blockers for
the treatment of patients with coronary artery disease
IVABRADINE IN CAD
•
Diminishes myocardial oxygen demand
•
Increases myocardial oxygen supply
•
Does not impair contractility
•
Does not affect ventricular relaxation
•
Allows coronary vasodilatation and coronary blood flow
Improves coronary perfusion and maintains cardiac performance better than alternative drug therapy
IVA is twice as effective as a beta-blocker for the same degree of HR reduction
GRAZIE PER L’ATTENZIONE
amacchi@aobusto.it
Gitt AK et al

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