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Ivabradine: Ivabradine: Is there a cardiovascular benefit to Is there a cardiovascular benefit to pure heart rate reduction?pure heart rate reduction?

Catheterization Conference

October 27, 2011

Anit Mankad, MD

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By Harlan Jay Ellison (1965)

“Heart Beat Hypothesis”

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Overview

Beta BlockersActivity, impact, intolerance

Adrenergic (sympathetic) activityIf current and “Funny” Channels

IvabradineEarly trials BEAUTIFUL and SHIFT trialsCurrent indications outside the U.S.

Future considerations

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Case

55 yo WM, PMH history of CAD s/p previous PCI, Ischemic cardiomyopathy, EF 35%, Severe COPD with frequent use of inhalers, comes to your clinic for follow-up, describing low grade stable angina for months (since PCI).

On metoprolol 6.25mg bid, amlodipine 10mg, asa, plavix, statin, ISMN 60mg

BP 110/60, HR 88 at rest. What can we offer him?

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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 Studyprogressive 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 MIstarting at HR > 70 (J Am Coll Cardiol 2007;50:823-30)

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Mechanism of Consequences of Elevated Resting Heart Rate

Increases myocardial oxygen demand Decreases myocardial perfusion by reducing

diastolic perfusion time (Circulation 1979;60:164-9)

Causes vasoconstriction of diseased coronary arteriesSambuceti et al. (Circulation. 1997; 95: 2652-9)

○ 10 patients found to have LAD stenosis (mean 80±5%) vs 7 controls with atypical chest pain, no significant CAD.

○ Pacer lead in RA, flow wire to calculate coronary resistance index○ AdenosinePacing (increments of 20bpm increase)

Adenosine

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Sambuceti G et al. Circulation 1997;95:2652-2659

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Heart Rate in Cardiovascular Outcomes

Diaz et al. 25,000 patients who had cardiac cath requests for

suspected or proven CADDivided heart rate into quintilesMultivariable Cox PH models

○ Adjusted for beta-blockers use As well as smoking, DM, HTN, gender, age, EF, antiplatelet

and lipid agents

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Beta-Adrenoceptors Endogenous

catecholamines

activate B-receptors

(Adenylate Cyclase)

Increased cAMP

Increased Ca++ influx

Inotropic Chronotropic

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Beta Blockers (BB) B1negative chronotropy and inotropyAV conduction delayReduced atrial and ventricular arrythmias

B2BronchoconstrictionPeripheral unopposed alpha constrictionDecrease glycogenolysis

- (contribute to hypoglycemic events) Other antagonize release of renin reduces intraocular pressures

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Impact of BB

Acute MINorwegian Multicenter

Study Group Timolol *CAPRICORN †ISIS-1 ‡

CHFCOPERNICUS £MERIT-HF €

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Intolerence of BB Side effects

Bronchoconstriction, AV delay, hypoglycemiaWeight gain, depression, fatigue

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 deleteriousThis has been shown in dogs (Eur Heart J (2004) 25 (7): 579-586

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Autonomic Nervous System

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If Current

Sinoatrial Node NA-K inward current Regulated by the

Funny ChannelcAMP

H.F.Brown (1979)• means for acceleration of diastolic depolarization (heart

rate) in adrenergic response

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Autonomic Nervous System

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Ivabradine Specifically binds the Funny

channelReduces the slope for diastolic

depolarization ○ Prolongs diastolic duration

Does not alter…○ Ventricular repolarization○ Myocardial contractility○ Blood pressure

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Ivabradine

2005--Approved by the European Medicine Agency Trade: Procoralan, Coralan (India), Corlentor (Italy)

2.5mg, 5mg, 7.5mg. Two times a day

Side Effects (%) Teratogenic

PregnancyBreast feeding

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Early Studies

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Heart rate Reduction during Exercise-inducedMyocardial Ischemia and Stunning

5 dogs with implanted LCx occluder, ultrasound crystals (LV wall thickness), and pacerIvabradine vs atenolol vs saline

○ Administered before or after 10min on treadmill ○ Paced at 150bpm for 6 hours

26Monnet X et al. Eur Heart J 2004;25:579-586

*P<0.05: atenolol and ivabradine significantly different from saline.

Saline (full circles) Ivabradine (open circles) Atenolol (open triangles)

Administration BEFORE Onset of Exercise

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Monnet X et al. Eur Heart J 2004;25:579-586

*P<0.05: atenolol and ivabradine significantly different from saline. †P<0.05: atenolol significantly different from ivabradine.

Saline (full circles) Ivabradine (open circles) Atenolol (open triangles)

Administration BEFORE Onset of Exercise AND PACED

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Monnet X et al. Eur Heart J 2004;25:579-586

Administration AFTER Onset of Exercise

*P<0.05: atenolol and ivabradine significantly different from saline. †P<0.05: atenolol significantly different from ivabradine.

Saline (full circles) Ivabradine (open circles) Atenolol (open triangles)

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Monnet X et al. Eur Heart J 2004;25:579-586

*P<0.05: atenolol and ivabradine significantly different from saline. †P<0.05: atenolol significantly different from ivabradine.

Administration AFTER Onset of ExerciseAND PACED

Saline (full circles) Ivabradine (open circles) Atenolol (open triangles)

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Ivabradine Trials

Reduces atherosclerosis (Circ 2008;117:2377-87)

Decreases vascular oxidative stressImproves endothelial function

Increases exertional tolerance and time to ischemia in patients with > 3 months angina (Circ 2003;107:817-23)

Non-inferior to Atenolol (Eur Heart J 2005;26:2529-36)

Exercise tolerance, time to angina or ischemia Non-inferior to Amlodipine (Drugs 2007;67(3):393-405)

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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 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)

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CV Death/ Heart Failure Admissions(HR >60)

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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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What Can We Conclude 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

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SHIFT Trial Randomized, double-blinded, placebo controlled 6,500 subjects

Male (76%), Caucasian (89%)Class II – IV heart failure, EF<35%, HR>70bpmAdmission 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.

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Beta Blocker use in SHIFT

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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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SHIFT Echo substudy

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What Can We Conclude from the SHIFT Trial?

In patients with all-cause cardiomyopathy (EF<35%), and heart rates > 70bpm,

While there was no difference total cardiovascular mortality,

Ivabradine reduces… 1. Mortality due to Heart Failure

2. Heart failure admissions

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Current IndicationsEuropean Medicines Agency

“Treatment of symptoms of long-term stable angina in adults (aged over 18 years) with coronary artery disease who have normal sinus rhythm.

It can be used in the following groupsPatients who cannot take or tolerate beta-blockersPatients whose disease is not controlled with beta-

blockers and whose heart rate is above 60bpm.”

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Future Considerations

Use of Ivabradine in the acute settingAcute myocardial infarctionUpon onset of congestive heart failure?

Diastolic heart failure?

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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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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

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Case

55 yo WM, PMH history of CAD s/p previous PCI, Ischemic cardiomyopathy, EF 35%, Severe COPD with frequent use of inhalers, comes to your clinic for follow-up, describing low grade stable angina for months (since PCI).

On metoprolol 6.25mg bid, amlodipine 10mg, asa, plavix, statin, ISMN 60mg

BP 110/60, HR 88 at rest. What can we offer him? Ivabradine

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Thank You!