1 Ivabradine: Is there a cardiovascular benefit to pure heart rate reduction? Catheterization Conference October 27, 2011 Anit Mankad, MD

2  By Harlan Jay Ellison (1965)  “Heart Beat Hypothesis”

3 Overview  Beta Blockers Activity, impact, intolerance  Adrenergic (sympathetic) activity I f current and “Funny” Channels  Ivabradine Early trials BEAUTIFUL and SHIFT trials Current indications outside the U.S.  Future considerations

4 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?

5 Elevated Resting Heart Rate  Accelerates production of atherosclerosis (Int J Cardiol 2008;126:302-12)  Associated with coronary plaque disruption (Circulation 2001;126: )  Framingham Study progressive increase in all cause and cardiovascular mortality in relation to antecedent HR (Am Heart J 1987; 113: )  Continuous increase in death rates in survivors of Acute MI starting at HR > 70 (J Am Coll Cardiol 2007;50:823-30)

6 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 arteries Sambuceti et al. (Circulation. 1997; 95: ) ○ 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 ○ Adenosine  Pacing (increments of 20bpm increase)  Adenosine

7. Sambuceti G et al. Circulation 1997;95:

8 Heart Rate in Cardiovascular Outcomes  Diaz et al. 25,000 patients who had cardiac cath requests for suspected or proven CAD Divided heart rate into quintiles Multivariable 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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14 Beta-Adrenoceptors  Endogenous catecholamines  activate B-receptors  ( Adenylate Cyclase)  Increased cAMP  Increased Ca ++ influx Inotropic Chronotropic

15 Beta Blockers (BB)  B1  negative chronotropy and inotropy   AV conduction delay   Reduced atrial and ventricular arrythmias  B2  Bronchoconstriction   Peripheral unopposed alpha constriction   Decrease glycogenolysis -(contribute to hypoglycemic events)   Other  antagonize release of renin   reduces intraocular pressures

16 Impact of BB  Acute MI Norwegian Multicenter Study Group Timolol * CAPRICORN † ISIS-1 ‡  CHF COPERNICUS £ MERIT-HF €

17 Intolerence of BB  Side effects Bronchoconstriction, AV delay, hypoglycemia Weight 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 deleterious This has been shown in dogs (Eur Heart J (2004) 25 (7):

18 Autonomic Nervous System

19 I f Current  Sinoatrial Node  NA-K inward current  Regulated by the Funny Channel cAMP  H.F.Brown (1979) means for acceleration of diastolic depolarization (heart rate) in adrenergic response

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21 Autonomic Nervous System

22 Ivabradine  Specifically binds the Funny channel Reduces the slope for diastolic depolarization ○ Prolongs diastolic duration  Does not alter… ○ Ventricular repolarization ○ Myocardial contractility ○ Blood pressure

23 Ivabradine  Approved by the European Medicine Agency  Trade: Procoralan, Coralan (India), Corlentor (Italy)  2.5mg, 5mg, 7.5mg. Two times a day  Side Effects (%)  Teratogenic Pregnancy Breast feeding

24 Early Studies

25 Heart rate Reduction during Exercise-induced Myocardial Ischemia and Stunning  5 dogs with implanted LCx occluder, ultrasound crystals (LV wall thickness), and pacer Ivabradine vs atenolol vs saline ○ Administered before or after 10min on treadmill ○ Paced at 150bpm for 6 hours

26 Monnet X et al. Eur Heart J 2004;25: *P<0.05: atenolol and ivabradine significantly different from saline. Saline (full circles) Ivabradine (open circles) Atenolol (open triangles) Administration BEFORE Onset of Exercise

27 Monnet X et al. Eur Heart J 2004;25: *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

28 Monnet X et al. Eur Heart J 2004;25: 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)

29 Monnet X et al. Eur Heart J 2004;25: *P<0.05: atenolol and ivabradine significantly different from saline. †P<0.05: atenolol significantly different from ivabradine. Administration AFTER Onset of Exercise AND PACED Saline (full circles) Ivabradine (open circles) Atenolol (open triangles)

30 Ivabradine Trials  Reduces atherosclerosis (Circ 2008;117: ) Decreases vascular oxidative stress Improves 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: ) Exercise tolerance, time to angina or ischemia  Non-inferior to Amlodipine (Drugs 2007;67(3): )

31 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)

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33 CV Death/ Heart Failure Admissions (HR >60)

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

35 Heart Failure Admissions (HR >70)

36 Acute MI Admissions (HR >70)

37 Proportion Requiring PCI (HR >70)

38 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

39 SHIFT Trial  Randomized, double-blinded, placebo controlled  6,500 subjects Male (76%), Caucasian (89%) Class II – IV heart failure, EF 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.

40 Beta Blocker use in SHIFT

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43 Cardiovascular Death and Heart Failure Admissions

44 Heart Failure Admissions

45 Cardiovascular Mortality

46 Deaths due to Heart Failure

47 SHIFT Echo substudy

48 What Can We Conclude from the SHIFT Trial?  In patients with all-cause cardiomyopathy (EF 70bpm,   While there was no difference total cardiovascular mortality,  Ivabradine reduces… 1. Mortality due to Heart Failure 2. Heart failure admissions

49 Current Indications European 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 groups Patients who cannot take or tolerate beta-blockers Patients whose disease is not controlled with beta- blockers and whose heart rate is above 60bpm.”

50 Future Considerations  Use of Ivabradine in the acute setting Acute myocardial infarction Upon onset of congestive heart failure?  Diastolic heart failure?

51 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.

52 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 70bpm,  Ivabradine reduces… 1. Mortality due to Heart Failure 2. Heart Failure Admissions

53 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

54 Thank You!