Dr. Tanveer

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-D27Published on behalf of the European Society of Cardiology. All rights reserved. The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org

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-D27Published on behalf of the European Society of Cardiology. All rights reserved. The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org

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

*Intolerence of BBSide effectsBronchoconstriction, AV delay, Hypoglycemia,hyperglycemia, dylipidemiaWeight gain, depression, fatigueClaudication in PADErrectile 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

IvabradineSpecifically binds the Funny channelReduces the slope for diastolic depolarization Prolongs diastolic duration

Does not alterVentricular repolarizationMyocardial contractilityBlood pressure

Contraindications: 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 IfApproximately 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.

There were no rebound or tolerance phenomena

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

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-feedingFertilityStudies in rats have shown no effect on fertility in males and females

InteractionPharmacodynamic interactionsQT prolonging medicinal productsPharmacokinetic interactionsCYP3A4 inhibitors - azoles, grape juiceCYP3A4 inducers - rifampicin, barbiturates, phenytoin,

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

Clinical trials of Ivabradine

BEAUTIFUL Trial (morBidity-mortality EvAlUaTion of the If inhibitor)

Randomized, double-blinded, placebo controlled781 centers, 33 countries 11,000 subjects (between 2005 and 2007) Male (98%), Caucasian (83%), HR>60, EF60 at 2 weeks, increase to 7.5mgPrimary endpoint was a composite of CV death and hospitalizations for MI or CHF

*CV Death/ Heart Failure Admissions(HR >70)

*Heart Failure Admissions(HR >70)

*Acute MI Admissions(HR >70)

*Proportion Requiring PCI(HR >70)

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)Acute Myocardial InfarctionCoronary Revascularization

SHIFT Trial(Systolic Heart Failure Treatment with If Inhibitor.)Randomized, double-blinded, placebo controlled6,500 subjectsMale (76%), Caucasian (89%)Class II IV heart failure, EF70bpmAdmission for heart failure in the previous 2 monthsOn optimal medical management90% on BB, 84% on ACE/ARBs, 60% Aldo antagonistsIvabradine vs placebo, followed for 3 yearsPrimary endpoint: composite of CV death or hospital admission for heart failure.

*Cardiovascular Death and Heart Failure Admissions

Heart Failure Admissions

*Cardiovascular Mortality

Deaths due to Heart Failure

Conclusions from the SHIFT Trial In patients with all-cause cardiomyopathy (EF 70bpm, There was no difference total cardiovascular mortality

Ivabradine reduces Mortality due to Heart FailureHeart failure admissions

Tardif J-C et al. Eur Heart J. 2005;26:2529-36.ET = exercise test (treadmill) *ET at trough and 4 hours post-doseInternational Trial on the Treatment of Angina with Ivabradine vs. Atenolol

INITIATIVE: SummaryIvabradine 7.5 mg bid and 10 mg bid were noninferior to atenolol 100 mg as measured byTotal exercise durationTime to limiting angina, angina onset, and 1 mm STMost common adverse events were transient visual symptoms, mainly increased brightness in limited areasSinus bradycardia occurred in 2.2% (ivabradine 7.5 mg), 5.4% (ivabradine 10 mg), and 4.3% (atenolol) of patientsIf current inhibition may be as effective as -blockade in treatment of stable anginaTardif J-C et al. Eur Heart J. 2005;26:2529-36.

ASSOCIATE :(evaluation of the Antianginal efficacy and Safety of the aSsociation Of the If Current InhibitorivAbradinewith a beTa-blockEr)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 HFSo SIGNIfY will be a logical extension ofBEAUTIfUL.

VIVIFYVIVIfY

This was a multicenter randomized double-blind placebo-controlled trialpatients aged 4080 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 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.

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.

SummaryIvabradine use reduces readmissions due to coronary artery disease (when resting heart rate > 70, EF

Guidelines For Use

*INITIATIVE: Study designBorer JS, Fox K, Jaillon P, Lerebours G, for the Ivabradine Investigators Group. Antianginal and antiischemic effects of ivabradine, an If inhibitor, in stable angina: A randomized, double-blind, multicentered, placebo-controlled trial. Circulation. 2003;107:817-823.Sulfi S, Timmis AD. Ivabradine the first selective sinus node If channel inhibitor in the treatment of stable angina. Int J Clin Pract. 2006;60:222-228.*INITIATIVE: SummaryFrishman WH, Pepine CJ, Weiss RJ, Baiker WM. Addition of zatebradine, a direct sinus node inhibitor, provides no greater exercise tolerance benefit in patients with angina taking extended-release nifedipine: Results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group study. The Zatebradine Study Group. J Am Coll Cardiol. 1995;26:305-312.