Dr.

Tanveer
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 pre-existing
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
7
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
Ivabradine
Specifically binds the Funny channel
Reduces the slope for diastolic
depolarization
Prolongs diastolic duration

Does not alter
Ventricular repolarization
Myocardial contractility
Blood pressure
Contraindications:

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.
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
Special population
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,
Therapeutic indications
Treatment of coronary artery disease
Treatment of chronic heart failure
In inappropriate sinus tachycardia


Clinical trials of Ivabradine
BEAUTIFUL Trial (morBidity-mortality EvAlUaTion of the If
inhibitor)

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
22
CV Death/ Heart Failure Admissions
(HR >70)
23
Heart Failure Admissions
(HR >70)
24
Acute MI Admissions
(HR >70)
25
Proportion Requiring PCI
(HR >70)
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
SHIFT Trial(Systolic Heart Failure Treatment
with If Inhibitor.)
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.
29
Cardiovascular Death and Heart Failure
Admissions

Heart Failure Admissions

31
Cardiovascular Mortality

Deaths due to Heart Failure

Conclusions from the SHIFT Trial
In patients with all-cause cardiomyopathy (EF<35%),
and heart rates > 70bpm,

There was no difference total cardiovascular
mortality

Ivabradine reduces
1. Mortality due to Heart Failure
2. Heart failure admissions
INITIATIVE: Study design
Tardif J-C et al. Eur Heart J. 2005;26:2529-36.
ET = exercise test (treadmill)
*ET at trough and 4 hours post-dose
4 weeks 12 weeks 2 weeks
Atenolol
50 mg
(n = 307)
Ivabradine
5 mg bid
(n = 315)
Ivabradine
5 mg bid
(n = 317)
10 mg bid
7.5 mg bid
100 mg
50 mg
25 mg
Placebo
Placebo
7 days 27 days
Washout
Run-in
Selection ET
Inclusion ET ET* ET*
Placebo
International Trial on the Treatment of Angina with Ivabradine vs. Atenolol
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
I
f
current inhibition may be as effective as -blockade
in treatment of stable angina
Tardif J-C et al. Eur Heart J. 2005;26:2529-36.
ASSOCIATE :(evaluation of the Antianginal efficacy and
Safety of the aSsociation Of the If Current
Inhibitor ivAbradine with a beTa-blockEr)
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 4080 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 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.
Summary

Ivabradine is a selective inhibitor of Funny (I
f
)
Current in the sinoatrial node.

It causes a pure heart rate reduction.

It is shows cardiovascular benefit when given addition
to optimal medical management.
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



Guidelines For Use