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


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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

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]

HR controlBeta blockersCCBFunny channel blockers


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


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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


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.


The HCN Channel Familyhyperpolarization-activated cyclic nucleotide gated (HCN)channels


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If Current

Sinoatrial NodeNa -K inward

currentRegulated by

cAMPVoltage


+ +

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.


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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


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


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)


Side effects


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.


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

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]


Therapeutic indicationsTreatment of coronary artery diseaseTreatment of chronic heart failureIn inappropriate sinus tachycardia


Clinical trials of ivabradine


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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)


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Heart Failure Admissions(HR >70)


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Acute MI Admissions(HR >70)


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Proportion Requiring PCI(HR >70)


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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


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


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.


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.



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.


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.


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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


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Heart Failure Admissions


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Cardiovascular Mortality


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Deaths due to Heart Failure


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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 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.


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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 review

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