Ivabradine:
Is there a cardiovascular benefit to
pure heart rate reduction?
Catheterization Conference
October 27, 2011
Anit Mankad, MD
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 By
Harlan Jay Ellison (1965)
 “Heart
Beat Hypothesis”
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Overview
 Beta
Blockers
 Activity, impact, intolerance
 Adrenergic
(sympathetic) activity
 If current and “Funny” Channels
 Ivabradine
 Early trials
 BEAUTIFUL and SHIFT trials
 Current indications outside the U.S.
 Future
considerations
3
Case
 55
yo WM, PMH history of CAD s/p previous
PCI, Ischemic cardiomyopathy, EF 35%,
Severe COPD with frequent use of inhalers,
comes to your clinic for follow-up, describing
low grade stable angina for months (since
PCI).
On metoprolol 6.25mg bid, amlodipine 10mg,
asa, plavix, statin, ISMN 60mg
 BP 110/60, HR 88 at rest.
 What can we offer him?

4
Elevated Resting Heart Rate
 Accelerates
production of atherosclerosis (Int
J Cardiol 2008;126:302-12)
 Associated with coronary plaque disruption
(Circulation 2001;126:1477-82)
 Framingham Study
 progressive increase in all cause and cardiovascular
mortality in relation to antecedent HR (Am Heart J 1987;
113:1489-94)
 Continuous
increase in death rates in
survivors of Acute MI
 starting at HR > 70 (J Am Coll Cardiol 2007;50:823-30)
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Mechanism of Consequences of
Elevated Resting Heart Rate
 Increases
myocardial oxygen demand
 Decreases myocardial perfusion by reducing
diastolic perfusion time (Circulation 1979;60:1649)
 Causes vasoconstriction of diseased coronary
arteries
 Sambuceti et al. (Circulation. 1997; 95: 2652-9)
○ 10 patients found to have LAD stenosis (mean 80±5%) vs 7 controls
with atypical chest pain, no significant CAD.
○ Pacer lead in RA, flow wire to calculate coronary resistance index
○ AdenosinePacing (increments of 20bpm increase)
Adenosine
6
.
Sambuceti G et al. Circulation 1997;95:2652-2659
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Heart Rate in Cardiovascular
Outcomes
 Diaz
et al.
 25,000 patients who had cardiac cath requests for
suspected or proven CAD
 Divided heart rate into quintiles
 Multivariable Cox PH models
○ Adjusted for beta-blockers use
 As well as smoking, DM, HTN, gender, age, EF, antiplatelet
and lipid agents
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Beta-Adrenoceptors
Endogenous
catecholamines
 activate B-receptors


(Adenylate Cyclase)
 Increased
cAMP
 Increased
Ca++ influx
Inotropic
Chronotropic
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Beta Blockers (BB)
B1negative chronotropy and inotropy
 AV conduction delay
 Reduced atrial and ventricular
arrythmias

B2Bronchoconstriction
 Peripheral unopposed alpha
constriction
 Decrease glycogenolysis

- (contribute to hypoglycemic events)

Other antagonize release of renin

reduces intraocular pressures

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Impact of BB
 Acute MI
 Norwegian Multicenter
Study Group Timolol *
 CAPRICORN †
 ISIS-1 ‡
 CHF
 COPERNICUS £
 MERIT-HF €
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Intolerence of BB

Side effects
 Bronchoconstriction, AV delay, hypoglycemia
 Weight gain, depression, fatigue

BB may not be tolerated in high enough doses to
attain heart rates below 70bpm

Acute setting (Acute MI, or CHF), the negative
inotropic effect could be deleterious
 This has been shown in dogs
(Eur Heart J (2004) 25 (7): 579-586
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Autonomic Nervous System
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If Current
H.F.Brown
(1979)
• means for acceleration of diastolic depolarization (heart
rate) in adrenergic response
Sinoatrial Node
 NA-K inward current
 Regulated by the
Funny Channel

 cAMP
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Autonomic Nervous System
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Ivabradine
 Specifically
binds the Funny
channel
 Reduces the slope for diastolic
depolarization
○ Prolongs diastolic duration

Does not alter…
○ Ventricular repolarization
○ Myocardial contractility
○ Blood pressure
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Ivabradine
 2005--Approved
by the European Medicine Agency
 Trade: Procoralan, Coralan (India), Corlentor (Italy)
 2.5mg, 5mg, 7.5mg. Two times a day

Side Effects (%)
 Teratogenic
 Pregnancy
 Breast feeding
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Early Studies
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Heart rate Reduction during Exercise-induced
Myocardial Ischemia and Stunning

5 dogs with implanted LCx occluder, ultrasound
crystals (LV wall thickness), and pacer
 Ivabradine vs atenolol vs saline
○ Administered before or after 10min on treadmill
○ Paced at 150bpm for 6 hours
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Administration BEFORE Onset of Exercise
Saline
(full circles)
Ivabradine (open circles)
Atenolol (open triangles)
*P<0.05: atenolol and ivabradine significantly different from saline.
Monnet X et al. Eur Heart J 2004;25:579-586
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Administration BEFORE Onset of Exercise
AND PACED
Saline
(full circles)
Ivabradine (open circles)
Atenolol (open triangles)
*P<0.05: atenolol and ivabradine significantly different from saline.
†P<0.05: atenolol significantly different from ivabradine.
Monnet X et al. Eur Heart J 2004;25:579-586
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Administration AFTER Onset of Exercise
Saline
(full circles)
Ivabradine (open circles)
Atenolol (open triangles)
*P<0.05: atenolol and ivabradine significantly different from saline.
†P<0.05: atenolol significantly different from ivabradine.
Monnet X et al. Eur Heart J 2004;25:579-586
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Administration AFTER Onset of Exercise
AND PACED
Saline
(full circles)
Ivabradine (open circles)
Atenolol (open triangles)
*P<0.05: atenolol and ivabradine significantly different from saline.
†P<0.05: atenolol significantly different from ivabradine.
Monnet X et al. Eur Heart J 2004;25:579-586
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Ivabradine Trials
 Reduces
atherosclerosis (Circ 2008;117:2377-
87)
 Decreases vascular oxidative stress
 Improves endothelial function
 Increases
exertional tolerance and time to
ischemia in patients with > 3 months angina
(Circ 2003;107:817-23)
 Non-inferior to Atenolol (Eur Heart J
2005;26:2529-36)
 Exercise tolerance, time to angina or ischemia
 Non-inferior
to Amlodipine (Drugs
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BEAUTIFUL Trial

Randomized, double-blinded, placebo controlled
 781 centers, 33 countries
 11,000
subjects (between 2005 and 2007)
 Male (98%), Caucasian (83%), HR>60, EF<40%
 CAD and on optimal medical management
○ 87% on BB, 89% on ACE/ARBs, 27% Aldo antagonists
 Ivabradine
vs placebo, followed for 3 years
 5mg bid, if HR >60 at 2 weeks, increase to 7.5mg
 Primary
endpoint was a composite of CV death
and hospitalizations for MI or CHF
 Subgroup analysis: HR>70 (5,400)
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CV Death/ Heart Failure Admissions
(HR >60)
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CV Death/ Heart Failure Admissions
(HR >70)
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Heart Failure Admissions
(HR >70)
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Acute MI Admissions
(HR >70)
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Proportion Requiring PCI
(HR >70)
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What Can We Conclude from the
BEAUTIFUL Trial?
 While
there was no difference total
cardiovascular mortality


Ivabradine use appears to be a benefit in
reducing readmissions due to coronary artery
disease (when resting heart rate > 70)
1. Acute Myocardial Infarction
2. Coronary Revascularization
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SHIFT Trial
Randomized, double-blinded, placebo controlled
 6,500 subjects

 Male (76%), Caucasian (89%)
 Class II – IV heart failure, EF<35%, HR>70bpm
 Admission for heart failure in the previous 2 months
 On
optimal medical management
○ 90% on BB, 84% on ACE/ARBs, 60% Aldo antagonists
Ivabradine vs placebo, followed for 3 years
 Primary endpoint: composite of CV death or
hospital admission for heart failure.

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Beta Blocker use in SHIFT
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Cardiovascular Death and Heart
Failure Admissions
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Heart Failure Admissions
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Cardiovascular Mortality
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Deaths due to Heart Failure
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SHIFT Echo substudy
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What Can We Conclude from the
SHIFT Trial?
 In
patients with all-cause cardiomyopathy
(EF<35%), and heart rates > 70bpm,



While there was no difference total
cardiovascular mortality,
Ivabradine reduces…
1. Mortality due to Heart Failure
2. Heart failure admissions
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Current Indications
European Medicines Agency
 “Treatment
of symptoms of long-term stable
angina in adults (aged over 18 years) with
coronary artery disease who have normal sinus
rhythm.
 It can be used in the following groups
 Patients who cannot take or tolerate beta-blockers
 Patients whose disease is not controlled with beta-
blockers and whose heart rate is above 60bpm.”
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Future Considerations
 Use
of Ivabradine in the acute setting
 Acute myocardial infarction
 Upon onset of congestive heart failure?
 Diastolic
heart failure?
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Summary
 Ivabradine
is a selective inhibitor of “Funny”
(If) Current in the sinoatrial node.
 It
causes a pure heart rate reduction.
 It
is shows cardiovascular benefit when given
addition to optimal medical management.
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Summary
 Ivabradine
use reduces readmissions due to
coronary artery disease (when resting heart
rate > 70, EF<40%)
1. Acute Myocardial Infarction
2. Coronary Revascularization
 In
patients with all-cause cardiomyopathy
(EF<35%), and heart rates > 70bpm,

Ivabradine reduces…
1. Mortality due to Heart Failure
2. Heart Failure Admissions
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Case
 55
yo WM, PMH history of CAD s/p previous
PCI, Ischemic cardiomyopathy, EF 35%,
Severe COPD with frequent use of inhalers,
comes to your clinic for follow-up, describing
low grade stable angina for months (since
PCI).
On metoprolol 6.25mg bid, amlodipine 10mg,
asa, plavix, statin, ISMN 60mg
 BP 110/60, HR 88 at rest.
 What can we offer him?

Ivabradine
53
Thank You!
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