Ivabradine review

Out line
HR AND ITS PATHOPHYSIOLOGY
HR CONTROL
If CURRENT AS TARGET FOR HR CONTROL
IVABRADINE – PHARMOCOLOGY
EVIDENCE FOR USE (TRAILS)
SUMMARY OF TRAILS
GUIDELINES FOR USE

ivabradine - a short review

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)


3

Total and cardiovascular mortality according to resting heart rate: multivariate Cox
regression survival analysis for 24 913 patients with suspected or proven coronary artery
disease in the Coronary Artery Surgery Study (CASS).

Ferrari R Eur Heart J Suppl 2009;11:D19-D27
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author
2009. For permissions please email: journals.permissions@oxfordjournals.org

Rate of coronary artery disease mortality and sudden cardiac death (adjusted for
cardiovascular risk factors) according to resting heart rate values in men without preexisting coronary artery disease.

Ferrari R Eur Heart J Suppl 2009;11:D19-D27
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author
2009. For permissions please email: journals.permissions@oxfordjournals.org

HR control
Beta blockers
CCB
Funny channel blockers


Beta blockers
Antianginal effect
Improve prognosis in patients in heart failure or a

history of myocardial infarction.

 in many patients with coronary artery disease and left

ventricular systolic dysfunction, contraindications or
intolerance to recommended doses prevent adequate
heart rate reduction


Intolerence of BB
 Side effects

 Bronchoconstriction,
 AV delay,
 Hypoglycemia,hyperglycemia, dylipidemia
 Weight gain, depression, fatigue
 Claudication in PAD
 Errectile dysfunction

 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


12

Funny channels
When first described in the rabbit cardiac SAN,
 The current resulting from the activation of HCN

channels was called funny (If) because it is activated
by hyperpolarization, unlike other voltagedependent currents.


The HCN Channel Family

hyperpolarization-activated cyclic nucleotide gated (HCN)channels


If Current

 Sinoatrial Node
+ +
 Na -K inward

current
 Regulated by
cAMP
Voltage


17

The growing evidence for the potential clinical

benefits of pure heart rate-lowering drugs, together
with the primary role of the If current in the control
of heart rate demonstrated by recent progress in the
understanding of cardiac automaticity, prompted the
search for specific heart rate-lowering agents
targeting this current
Ivabradine is currently undergoing regulatory
approval Other agents such as zatebradine,
cilobradine and ZD 7288 have been investigated.

Ivabradine
 Specifically binds the Funny channel
Reduces the slope for diastolic

depolarization


Prolongs diastolic duration

Does not alter…
 Ventricular

repolarization
 Myocardial contractility
 Blood pressure


26

 Because it binds to the F channel in the open position, it has greatest

activity when there is greater open-close cycling of the F channel.
• Hence it exhibits is greatest effect when heart rates are highest.
• In that sense it has a partial self limiting capability .


Pharmacokinetics
It is rapidly absorbed (tmax=0.75–1.5 hours) with a

bioavailability of 37% to 49%.
Ivabradine has extensive tissue distribution with
70% protein binding.
It is extensively metabolized by the cytochrome P450 3A4
into several metabolites, including the N-demethylated
derivate, which is the major active metabolite. The
elimination process occurs by both fecal and urinary
pathways.
The main half-life of ivabradine is 2 hours, whereas that
of its N-demethylated metabolite is 13 hours

c/i
 Pre-existing bradycardia; ivabradine should not be

initiated if resting heart rate is less than 60 beats per
minute
Cardiogenic shock
 Sinoatrial disease (“sick sinus syndrome”)
 Class II or complete AV block
 Severe renal or hepatic impairment
 Pregnancy or breast feeding
 Atrial fibrillation (ineffective)

Side effects


SE
VISUAL SE
 Dose-related visual symptoms, the majority being

phosphene-like events (luminous phenomena).
These effects have been most frequent with high doses
(10 mg twice daily), are transient and always reversible
and are related to the action of the drug on retinal
HCN1 channels, similar to those mediating If
Approximately 15% of patients receiving the highest dose
(10 mg bid) and 2% of patients receiving the 5 and 2.5 mg
doses.

Bradycardia
Reported by 3.3% of patients particularly within the

first 2 to 3 months of treatment initiation.
0.5% of patients experienced a severe bradycardia
below or equal to 40 bpm


Overdose
Overdose may lead to severe and prolonged

bradycardia .

Severe bradycardia should be treated symptomatically
In the event of bradycardia with poor haemodynamic

tolerance, symptomatic treatment including
intravenous beta stimulating medicinal products such
as isoprenaline may be considered.
Temporary cardiac electrical pacing may be instituted if
required.


Special population

Elderly -

 >75 yrs , a lower starting dose should be considered (2.5 mg twice

daily ) before up-titration .

Renal impairment  No dose adjustment -- cr cl >15 ml/min .
 No data are available in patients with cr cl <15 ml/min. Ivabradine

should be used with precaution

Hepatic impairment
 No dose adjustment - mild hepatic impairment.
 Caution - moderate hepatic impairment.
 Contraindicated - severe hepatic insufficiency, since it has not

been studied in this population .

Paediatric population
 The safety and efficacy of ivabradine in children <18 years have not

yet been established.No data are available

Pregnancy
no or limited amount of data .
Studies in animals have shown reproductive toxicity.

These studies have shown embryotoxic and teratogenic
effects .
The potential risk for humans is unknown. Therefore,
ivabradine is contra-indicated during pregnancy

Breastfeeding
Animal studies indicate that ivabradine is excreted in

milk.Therefore,contraindicated during breast-feeding

Fertility
Studies in rats have shown no effect on fertility in males

and females


Interaction
Pharmacodynamic interactions
QT prolonging medicinal products

Pharmacokinetic interactions
CYP3A4 inhibitors - azoles, grape juice
CYP3A4 inducers - rifampicin, barbiturates, phenytoin,

Hypericum perforatum [St John’s Wort]


Therapeutic indications
Treatment of coronary artery disease
Treatment of chronic heart failure
In inappropriate sinus tachycardia


Clinical trials of ivabradine


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)

43

BEAUTIfUL trail

CV Death/ Heart Failure Admissions
(HR >70)


45

Heart Failure Admissions
(HR >70)


46

Acute MI Admissions
(HR >70)


47

Proportion Requiring PCI
(HR >70)


48

Conclusions 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


49

International Trial on the Treatment of Angina with Ivabradine vs. Atenolol
Ivabradine
5 mg bid
(n = 317)

10 mg bid

Ivabradine
5 mg bid
(n = 315)

7.5 mg bid

Placebo

Placebo

Placebo
7 days
2–7 days
Washout Run-in
Selection ET

4 weeks
Atenolol
50 mg
(n = 307)

Inclusion ET

12 weeks
100 mg

ET*

ET = exercise test (treadmill)
*ET at trough and 4 hours post-dose

2 weeks
50 mg
25 mg
ET*

Tardif J-C et al. Eur Heart J. 2005;26:2529-36.

INITIATIVE: Summary
 Ivabradine 7.5 mg bid and 10 mg bid were noninferior to atenolol 100

mg as measured by

 Total exercise duration
 Time to limiting angina, angina onset, and 1 mm ST↓

 Most common adverse events were transient visual symptoms, mainly

increased brightness in limited areas
 Sinus bradycardia occurred in 2.2% (ivabradine 7.5 mg),
5.4% (ivabradine 10 mg), and 4.3% (atenolol) of patients

If current inhibition may be as effective as β-blockade
in treatment of stable angina
Tardif J-C et al. Eur Heart J. 2005;26:2529-36.

Investigated the effects of ivabradine in patients with

stable angina receiving atenolol.
889 patients with stable angina receiving atenolol 50
mg/day were randomized to ivabradine 5 mg b.i.d. for
2 months, increased to 7.5 mg b.i.d. for a further 2
months, or placebo.


SIGNIfY will verify as it will enrol CAD patients with a

resting HR 70 b.p.m. and an ejection fraction >40%
without clinical symptoms of HF
So SIGNIfY will be a logical extension ofBEAUTIfUL.


VIVIFY


VIVIfY

This was a multicenter randomized double-blind

placebo-controlled trial
patients aged 40–80 years were randomized after
successful primary percutaneous coronary
intervention (PCI) performed within 6 h of STEMI
symptom onset.
Patients were in sinus rhythm and with heart rate >80
bpm and systolic blood pressure >90mm Hg.
They were randomly assigned (2:1 ratio) to
intravenous ivabradine (n=82) (5 mg bolus over 30 s,
followed by 5 mg infusion over 8 hr) or matching
placebo (n=42)
The primary outcome measure was heart rate and
blood pressure.

Conclusion:This pilot study shows that intravenous

ivabradine may be used safely to slow the heart rate in
STEMI. Further studies are needed to characterize its
effect on infarct size, left ventricular function and
clinical outcomes in this population.


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.

61

Cardiovascular Death and Heart Failure
Admissions


63

Heart Failure Admissions


64

Cardiovascular Mortality


65

Deaths due to Heart Failure


66

Conclusions from the SHIFT Trial
 In patients with all-cause cardiomyopathy (EF<35%),

and heart rates > 70bpm,

 There was no difference total

cardiovascularmortality



Ivabradine reduces…

1. Mortality due to Heart Failure
2. Heart failure admissions

67

ivabradine significantly improved symptoms

associated with inappropriate sinus tachycardia
 completely eliminated them in approximately half of
the patients.
These findings suggest that ivabradine may be an
important agent for improving symptoms in patients
with inappropriate sinus tachycardia.


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.


70

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

71

Ivabradine review

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