2. 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
3. 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)
ivabradine - a short review
3
9. 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
11. 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
ivabradine - a short review
12. 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 - a short review
12
13. 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
14. 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.
ivabradine - a short review
21. 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 - a short review
23. 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
24. Ivabradine
Specifically binds the Funny channel
Reduces the slope for diastolic
depolarization
Prolongs diastolic duration
Does not alter…
Ventricular
repolarization
Myocardial contractility
Blood pressure
ivabradine - a short review
26
25. 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 .
ivabradine - a short review
26. 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
ivabradine - a short review
27. 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)
ivabradine - a short review
29. 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.
ivabradine - a short review
30. 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
ivabradine - a short review
31. 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.
ivabradine - a short review
32. 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
ivabradine - a short review
33. 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
ivabradine - a short review
35. Therapeutic indications
Treatment of coronary artery disease
Treatment of chronic heart failure
In inappropriate sinus tachycardia
ivabradine - a short review
36. 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
39. 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)
ivabradine - a short review
43
45. 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
ivabradine - a short review
49
46. 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
ivabradine - a short review
2 weeks
50 mg
25 mg
ET*
Tardif J-C et al. Eur Heart J. 2005;26:2529-36.
47. 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.
ivabradine - a short review
49. 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.
ivabradine - a short review
52. 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.
ivabradine - a short review
54. 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
ivabradine - a short review
blood pressure.
55. 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.
ivabradine - a short review
57. 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.
ivabradine - a short review
61
61. Deaths due to Heart Failure
ivabradine - a short review
66
62. 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
ivabradine - a short review
67
64. 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.
ivabradine - a short review
65. 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.
ivabradine - a short review
70
66. 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
ivabradine - a short review
71
67. 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
{"49":"In this group, PCI was reduced by 30% (p value of 0.016)\nThis can extrapolated for white males with history of CAD, EF below 40%, and with resting heart rates above 70.\n","44":"Elevated heart rate (70 b.p.m.) is a predictor of cardiovascular outcomes in a population with stable coronary artery disease and left ventricular dysfunction\n","61":"SHIFT: Systolic Heart Failure Treatment with If Inhibitor. \n","50":"Two clinical trials have assessed the antianginal efficacy of ivabradine. The first was a placebo-controlled evaluation.1 INITIATIVE (International Trial on the Treatment of Angina with Ivabradine vs Atenolol), the second, was a comparison of ivabradine and atenolol.2\nINITIATIVE was designed to evaluate the noninferiority of ivabradine vs atenolol in patients with class I to III angina.\nPlacebo washout of prior antianginal medications lasted from 2 to 7 days, depending on the half-life of the medication. Subjects then entered a 7-day qualifying period, after which they were randomized to atenolol 50 mg or ivabradine 5 mg.\nAfter 4 weeks, atenolol was increased to 100 mg and ivabradine to 7.5 mg or 10 mg and treatment was continued for an additional 12 weeks.\n","17":"“F” stands for “Funny”, named because of its unusual properties compared systems at the time.\nSinoatrial node, but also found in AV Node and Purkinji fibers.\n","12":"Target doses for many studies are between 150 to 200mg of metoprolol daily.\n","51":"The most common adverse events were mild, transient increases in brightness in limited areas of the visual field. These are likely related to the presence in the retina of ion channels with a similar structure as the If channels of the sinoatrial node.\nThe incidence of sinus bradycardia in ivabradine patients was similar to or lower than in atenolol patients.\nINITIATIVE demonstrates that If current inhibition may be as effective as beta-blockade in treatment of stable angina.\nHowever, an earlier study of If inhibition with zatebradine showed no benefit in patients with chronic stable angina.1 Further investigation of If inhibition as an antianginal strategy is needed before its role can be defined.\n","7":"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). Data from Diaz et al.25\n","63":"relative risk of the primary endpoint(cardiovascular death or hospital admission for worsening heart failure) fell by 18% compared with placebo treatment.\n","8":"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. Data from Jouven et al.19\n","3":"Circ journal: Heart rates greater than 80.\n","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.\nHence it exhibits is greatest effect when heart rates are highest. \nIn that sense it has a partial self limiting capability.\n","43":"(morBidity-mortality EvAlUaTion of the If inhibitor)\nBy the way, all groups, even the sub group analysis had identical baseline characteristics. \n"}
