Ivabradine review
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Transcript of Ivabradine review
ivabradine - a short review
Out lineHR AND ITS PATHOPHYSIOLOGYHR CONTROLIf CURRENT AS TARGET FOR HR CONTROLIVABRADINE – PHARMOCOLOGYEVIDENCE FOR USE (TRAILS)SUMMARY OF TRAILSGUIDELINES FOR USE
ivabradine - a short review
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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
ivabradine - a short review
ivabradine - a short review
ivabradine - a short review
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]
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]
Out lineHR AND ITS PATHOPHYSIOLOGYHR CONTROLIf CURRENT AS TARGET FOR HR CONTROLIVABRADINE – PHARMOCOLOGYEVIDENCE FOR USE (TRAILS)SUMMARY OF TRAILSGUIDELINES FOR USE
ivabradine - a short review
HR controlBeta blockersCCBFunny channel blockers
ivabradine - a short review
Beta blockersAntianginal 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
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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
Out lineHR AND ITS PATHOPHYSIOLOGYHR CONTROLIf CURRENT AS TARGET FOR HR CONTROLIVABRADINE – PHARMOCOLOGYEVIDENCE FOR USE (TRAILS)SUMMARY OF TRAILSGUIDELINES FOR USE
ivabradine - a short review
Funny channelsWhen 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
ivabradine - a short review
The HCN Channel Familyhyperpolarization-activated cyclic nucleotide gated (HCN)channels
ivabradine - a short review
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If Current
Sinoatrial NodeNa -K inward
currentRegulated by
cAMPVoltage
ivabradine - a short review
+ +
ivabradine - a short review
ivabradine - a short review
ivabradine - a short review
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
ivabradine - a short review
Out lineHR AND ITS PATHOPHYSIOLOGYHR CONTROLIf CURRENT AS TARGET FOR HR CONTROLIVABRADINE – PHARMOCOLOGYEVIDENCE FOR USE (TRAILS)SUMMARY OF TRAILSGUIDELINES FOR USE
ivabradine - a short review
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IvabradineSpecifically binds the Funny
channelReduces the slope for diastolic
depolarization Prolongs diastolic duration
Does not alter… Ventricular repolarization Myocardial contractility Blood pressure
ivabradine - a short review
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
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
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
Side effects
ivabradine - a short review
SEVISUAL 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
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
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
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
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
BreastfeedingAnimal studies indicate that ivabradine is excreted
in milk.Therefore,contraindicated during breast-feeding
FertilityStudies in rats have shown no effect on fertility in
males and femalesivabradine - a short review
InteractionPharmacodynamic interactions
QT prolonging medicinal productsPharmacokinetic interactions
CYP3A4 inhibitors - azoles, grape juiceCYP3A4 inducers - rifampicin, barbiturates,
phenytoin, Hypericum perforatum [St John’s Wort]
ivabradine - a short review
Therapeutic indicationsTreatment of coronary artery diseaseTreatment of chronic heart failureIn inappropriate sinus tachycardia
ivabradine - a short review
Out lineHR AND ITS PATHOPHYSIOLOGYHR CONTROLIf CURRENT AS TARGET FOR HR CONTROLIVABRADINE – PHARMOCOLOGYEVIDENCE FOR USE (TRAILS)SUMMARY OF TRAILSGUIDELINES FOR USE
ivabradine - a short review
Clinical trials of ivabradine
ivabradine - a short review
ivabradine - a short review
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BEAUTIFUL TrialRandomized, double-blinded, placebo
controlled781 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 years5mg 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
BEAUTIfUL trailivabradine - a short review
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CV Death/ Heart Failure Admissions(HR >70)
ivabradine - a short review
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Heart Failure Admissions(HR >70)
ivabradine - a short review
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Acute MI Admissions(HR >70)
ivabradine - a short review
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Proportion Requiring PCI(HR >70)
ivabradine - a short review
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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 Infarction2. Coronary Revascularization
ivabradine - a short review
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
Atenolol50 mg(n = 307)
Ivabradine5 mg bid(n = 315)
Ivabradine5 mg bid(n = 317)
10 mg bid
7.5 mg bid
100 mg 50 mg25 mg
Placebo
Placebo
7 days2–7 daysWashout Run-in
Selection ET
Inclusion ET ET* ET*
Placebo
International Trial on the Treatment of Angina with Ivabradine vs. Atenolol
ivabradine - a short review
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
ivabradine - a short review
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
ivabradine - a short review
ivabradine - a short review
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
ivabradine - a short review
VIVIFYVIVIfY
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
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
ivabradine - a short review
61
SHIFT TrialRandomized, double-blinded, placebo
controlled6,500 subjects
Male (76%), Caucasian (89%)Class II – IV heart failure, EF<35%, HR>70bpmAdmission for heart failure in the previous 2
monthsOn optimal medical management
90% on BB, 84% on ACE/ARBs, 60% Aldo antagonists
Ivabradine vs placebo, followed for 3 yearsPrimary endpoint: composite of CV death
or hospital admission for heart failure.ivabradine - a short review
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Cardiovascular Death and Heart Failure Admissions
ivabradine - a short review
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Heart Failure Admissions
ivabradine - a short review
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Cardiovascular Mortality
ivabradine - a short review
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Deaths due to Heart Failure
ivabradine - a short review
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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 Failure2. Heart failure admissions
ivabradine - a short review
ivabradine - a short review
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
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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.
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SummaryIvabradine use reduces readmissions due to
coronary artery disease (when resting heart rate > 70, EF<40%)1. Acute Myocardial Infarction2. Coronary Revascularization
In patients with all-cause cardiomyopathy (EF<35%), and heart rates > 70bpm,
Ivabradine reduces… 1. Mortality due to Heart Failure2. Heart Failure Admissions
ivabradine - a short review
Out lineHR AND ITS PATHOPHYSIOLOGYHR CONTROLIf CURRENT AS TARGET FOR HR CONTROLIVABRADINE – PHARMOCOLOGYEVIDENCE FOR USE (TRAILS)SUMMARY OF TRAILSGUIDELINES FOR USE
ivabradine - a short review
ivabradine - a short review
ivabradine - a short review