Weekly session on Ivabradine

1. IVABRADINE
MD.Mahamudul Hasan
Medical Officer
Cardiology,KYAMCH

2. IVABRADINE

3. Introduction
 Ivabradine, sold under the brand
name Ivanor among others, is a medication,
which is a pacemaker current (If) inhibitor, used
for the symptomatic management of
heart-related chest pain and heart failure.
Patients who qualify for use of Ivabradine for
coronary heart failure are patients who have
symptomatic heart failure, with reduced ejection
volume, and heart rate at least 70 bpm, and the
condition not able to be fully managed by
beta blockers.[2]

4. Cont.
 Ivabradine acts by allowing negative
chronotropy in the sinoatrial structure, thus
reducing the heart rate via specific inhibition of
the pacemaker current. It operates by a
mechanism different from that of beta blockers
and calcium channel blockers, which are two
commonly prescribed antianginal classes of
cardiac drugs. Ivabradine has no apparent
inotropic properties and may be a cardiotonic
agent.

5. Cont.

6. Lisensing status
The journey begins in 1979 with the discovery of
funny (If current)channel in the cells of the
sinus node of the heart.
 Ivabradine is the only benzazepine derivative
approved for clinical use by blocking if current
and was developed by sevier 20 years ago.
 • Ivabradine is approved by european
Medicine Agency in 2005 and by the United
States Food & Drug Adminastration in 2015.
.

7. Clinical trials

8. Cont.
 The BEAUTIFUL study randomised over
10917 patients having stable coronary artery
disease and left ventricle dysfunction
(ejection fraction < 40%). Ivabradine did not
show a significant reduction in the primary
composite endpoint of cardiovascular
death, admission to hospital for acute
myocardial infarction, and admission to
hospital for new onset or worsening heart
failure.

9. Cont.
 Coronary events by 22% (P=0.023)
 Fatal and nonfatal myocardial infarction by
36% (P=0.001)
 Coronary revascularization by 30% (P=0.016).
 These results were seen in combination
therapy with beta blockers, and were found
to be safe and effective in improving
coronary artery disease outcomes in patients
with heart rates of 70 bpm or more.[18]

10. Cont.
 The SIGNIFY trial randomised 19102 patients with
stable coronary artery disease and an elevated heart
rate greater than 70 beats per minute were assigned
to an intervention of ivabradine or placebo in
addition to standard therapy. Ivabradine did not
significantly improve the secondary outcomes in
patient groups, however did demonstrate a
reduction in heart rate. When compared to the
SHIFT study, a reduction in cardiovascular death or
hospital admission was also demonstrated and
hence should be considered when additional
therapy is in question.[19][20]

11. Cont.
 however did demonstrate a reduction in
heart rate. When compared to the SHIFT
study, a reduction in cardiovascular
death or hospital admission was also
demonstrated and hence should be
considered when additional therapy is in
question.[19][20]

12. Pharmacokinetics
 Absorption: Rapid(tmax=0.75 to 1.5 hours) with a
bioavailability of 37 to 49%
 Distribution: Extensive tissue distribution with 70%
protein binding capacity.
 Metabolism: Metabolized mainly by cytochrome P450 3A4
enzymes to several metabolites, including the N-
demethylated derivate,which is the major active
metabolite.
 Excretion: The elimination process occur by both fecal &
urinary pathways.
 Half-life: The main half life of Ivabradine is 2 hours,
whereas that of its N-demethylated metabolite is 13 hours.

13. Indications

14. Contrindications
•Pre-existing bradycardia; resting heart rate <60
bpm prior to treatment.
• Sinoatrial disease(Sick sinus syndrome).
• 3rd
degree or complete AV block.
• Pacemaker dependent.
• Acute decompensated heart failure.
• severe renal or hepatic impairment.
•Combination with strong CYP3A4 inhibitor.
•Pregnancy or breast feeding.

15. Side Effects
 Overall, 14.5% of patients taking ivabradine
experience luminous phenomena (by patients
described as sensations of enhanced brightness
in a fully maintained visual field). This is
probably due to blockage of Ih ion channels in
the retina, which are very similar to cardiac If.
These symptoms are mild, transient, and fully
reversible. In clinical studies, about 1% of all
patients had to discontinue the drug because of
these sensations, which occurred on average 40
days after the drug was started.[5]

16. Side Effects
 In a large clinical trial, bradycardia (unusually
slow heart rate) occurred in 2% and 5% of
patients taking ivabradine at doses of 7.5 and
10 mg respectively (compared to 4.3% in those
taking atenolol).[5]
Headaches were reported in
2.6 to 4.8 percent of cases.[5]
Other common
adverse drug reactions (1–10% of patients)
include first-degree AV block, ventricular
extrasystoles, dizziness and/or blurred vision.
[13]

17. Mechanism of Action

18. Mechanism of Action
 Ivabradine acts on the If (f is for "funny", so called
because it had unusual properties compared with other
current systems known at the time of its discovery) ion
current, which is highly expressed in the sinoatrial
node. If is a mixed Na+
–K+
inward current activated by
hyperpolarization and modulated by the autonomic
nervous system. It is one of the most important ionic
currents for regulating pacemaker activity in the
sinoatrial (SA) node. Ivabradine selectively inhibits the
pacemaker If current in a dose-dependent manner.
Blocking this channel reduces cardiac pacemaker
activity, selectively slowing the heart rate and
allowing more time for blood to flow to the

19. MECHANISM OF ACTION
 .[14][15]
By inhibiting the If channel, ivabradine reduces the
heart rate and workload on the heart. This is relevant in
the usage of the medication to treat angina as well as
congestive heart failure. This is in contrast to other
commonly used rate-reducing medications, such as beta-
blockers and calcium channel blockers, which not only
reduce heart rate, but also the cardiac contractility. Given
the selective decrease in rate without loss of contractility,
ivabradine may prove efficacious for treatment of
congestive heart failure with reduced ejection fraction.
 Ivabradine binds to HCN4 receptors (potassium/sodium
hyperpolarization-activated cyclic nucleotide-gated
channel 4), utilizing Y506, F509 and I510 residues.[16]

20. Dosages

21. Role of Ivabradne in heart failure
Role of Ivabradne in heart failure

22. Role of Ivabradne in heart failure
 Indicated to reduce the risk of hospitalization for
worsening heart failure in patients with stable,
symptomatic chronic heart failure with LVEF
≤35%, who are in sinus rhythm with resting heart
rate ≥70 bpm and either are on maximally
tolerated doses of beta-blockers or have a
contraindication to beta-blocker use
 Initial: 5 mg PO BID with meals
 After 2 weeks, assess patient and adjust dose to
achieve a resting heart rate of 50-60 bpm (see dose
adjustment section below)

23. Role of Ivabradne in heart failure
 Thereafter, adjust dose as needed based on resting
heart rate and tolerability; not to exceed 7.5 mg BID
 Dose adjustment
 HR >60 bpm: Increase dose by 2.5 mg (given BID)
up to a maximum dose of 7.5 mg BID
 HR 50-60 bpm: Maintain dose
 HR <50 bpm or signs and symptoms of
bradycardia: Decrease dose by 2.5 mg (given twice
daily); if current dose is 2.5 mg BID, discontinue
therapy

24. THANK YOU