Ivabradine review

1. ivabradine - a short review

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. 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

4. ivabradine - a short review

5. ivabradine - a short review

6. ivabradine - a short review

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).
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: [email protected]

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.
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: [email protected]

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

10. HR control
Beta blockers
CCB
Funny channel blockers
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. 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

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 voltage-
dependent currents.
ivabradine - a short review

15. ivabradine - a short review

16. The HCN Channel Family
hyperpolarization-activated cyclic nucleotide gated (HCN)channels
ivabradine - a short review

17. 17
I
f
Current
Sinoatrial Node
Na -K inward
current
Regulated by
cAMP
Voltage

ivabradine - a short review
++

18. ivabradine - a short review

19. ivabradine - a short review

20. 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

22. 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. 26
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

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

28. Side effects
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. 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
Special population

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

34. 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]
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

37. Clinical trials of ivabradine
ivabradine - a short review

38. ivabradine - a short review

39. 43
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

40. BEAUTIfUL trail
ivabradine - a short review

41. 45
CV Death/ Heart Failure Admissions
(HR >70)
ivabradine - a short review

42. 46
Heart Failure Admissions
(HR >70)
ivabradine - a short review

43. 47
Acute MI Admissions
(HR >70)
ivabradine - a short review

44. 48
Proportion Requiring PCI
(HR >70)
ivabradine - a short review

45. 49
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

46. 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 days2–7 days
WashoutRun-in
Selection ET
Inclusion ET ET* ET*
Placebo
International Trial on the Treatment of Angina with Ivabradine vs. Atenolol
ivabradine - a short review

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
I
f
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

48. 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

50. ivabradine - a short review

51. 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

53. ivabradine - a short review
VIVIFY
VIVIfY

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
blood pressure.ivabradine - a short review

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

56. ivabradine - a short review

57. 61
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

58. 63
Cardiovascular Death and Heart Failure
Admissions
ivabradine - a short review

59. 64
Heart Failure Admissions
ivabradine - a short review

60. 65
Cardiovascular Mortality
ivabradine - a short review

61. 66
Deaths due to Heart Failure
ivabradine - a short review

62. 67
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

63. ivabradine - a short review

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. 70
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.
ivabradine - a short review

66. 71
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

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

68. ivabradine - a short review

69. ivabradine - a short review