Heart rate a global target for cardiovascular disease and therapy along the cardiovascular disease...

Heart rate: A global target for cardiovascular disease and therapy along the

cardiovascular disease continuum

Prof Kyaw Soe WinMBBS, M.Med.Sc (Int.Med) MRCP (UK), FRCP (Edin),

Dr Med Sc (Cardiology), Dip Med Ed, FAsCC, FAPSIC, FESC, FACC

Fellowship in Interventional Cardiology ( Singapore)Senior Consultant Cardiologist, Mandalay General Hospital

Hotel Marvel 15th May 2016

CONCLUSION

• High resting heart rate is a predictor of mortality in a large variety of populations:

• General population• Prehypertensive patients• Hypertensive patients • Stable CAD patients• ACS patients• Post-MI patients • Heart failure patients

Ivabradine indicated for CAD patients

Symptomatic treatment of chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm:

•in patients with HR > 70 bpm- In addition to beta-blockers- As an alternative to beta-blockers

Indication approved by the European Medicines Agency, 02/2012

Ivabradine indicated for chronic heart failure

• Ivabradine is indicated in chronic heart failure NYHA II to IV class with systolic dysfunction, in patients in sinus rhythm and whose heart rate is ≥ 70 bpm

• In combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated

Heart rate : the first rhythm in our life

per day: 80 x 60 min x 24 h = 115.200 beats per year: 42.048.000 beats80 years: 3.363.840.000 beats

~300 mg ATP per beat~ 30 kg ATP per day

Heart Rate Reduction by 10 beatssaves ~ 5 kg ATP per day

Heart Rate – marker of metabolism

Ferrari et al. EHJ 2008, 10(Suppl) F7-10.

The story of Hummingbird and Turtle

Hummingbird:

- HR = 600 bpm

- lives 5 months

Turtle:

- HR = 6 bpm

- lives 150 years

Same number of heart beat in life: 500 million beats!

The Heart Rate and longevity throughout the whole animal kingdom

• A study of birds and nonhibernating mammals showed a linear relationship between the resting HR and longevity

• The only species to fall off the predicted line for longevity was men ( 30 yrs for stone aged men)

• Life span of modern westernized man is about 80 yrs because of improved living standard and medical advances.

The higher Heart rate; The shorter life span

I. High resting heart rate and mortality in General population & Hypertensive patients

II. Role of heart rate in development of atherosclerosisIII. Role of heart rate in stable coronary artery diseaseIV. Role of heart rate in acute coronary syndromeV. Role of heart rate in postmyocardial infarctionVI. Role of heart rate in chronic heart failureVII. New treatment option by slowing heart rate with Ivabradine

Effect of Ivabradine on Morbi-mortality in CAD Effect of Ivabradine on Morbi-mortality in CHFAnti-ischemic efficacy of Ivabradine in patients already treated with beta blockers

Outlines

I. High resting heart rate is an independent risk

factor for mortality in General population &

Hypertensive patients

Normal Population•Chicago Study- relationship between high HR and all-cause death and sudden CHD death¹. (1980)•Framingham study confirmed after 30 yrs follow-up. The relationship was stronger in men than women. (1987)•The results were confirmed by other three studies.

Mensink GB et al. Eur Heart J 1997;18:1404-10. Tverdal A et al. Eur Heart J 2008;29:2772-81. Jouven X et al. Eur Heart J 2009;103:279-83.

Resting Heart Rate as Prognostic indicators in non-Hypertensive subjects

Adapted from V. Aboyans et al. Adapted from V. Aboyans et al. Journal of Clinical EpidemiologyJournal of Clinical Epidemiology . 59 (2006) 547–558 . 59 (2006) 547–558

Chicago Gas Company ‘80 Chicago Gas Company ‘80 1,233 M1,233 M 15 y15 y >94 vs. >94 vs. <<60 bpm 60 bpm 2.32.3Chicago Heart Ass.Project ’80Chicago Heart Ass.Project ’80 33,781 M&W 33,781 M&W 22 y22 y >>90 vs. <70 bpm 90 vs. <70 bpm M: 1.6 W: 1.1 (ns)M: 1.6 W: 1.1 (ns)Framingham ‘93 Framingham ‘93 4,530 M&W HTN4,530 M&W HTN 36 y36 y >100 vs. <60 bpm >100 vs. <60 bpm M: 1.5 W: 1.4 (ns)M: 1.5 W: 1.4 (ns)British Regional Heart ’93British Regional Heart ’93 735 M735 M 8 y8 y >90 vs. >90 vs. <<90 bpm 90 bpm IHD death 3.3IHD death 3.3Spandau ’97Spandau ’97 4,756 M&W4,756 M&W 12 y12 y Sudden death Sudden death 5.2 per 20 bpm5.2 per 20 bpmBenetos ’99Benetos ’99 19,386 M&W19,386 M&W 18.2 y18.2 y >100 vs. <60 bpm >100 vs. <60 bpm M: 2.2 W: 1.1 (ns)M: 2.2 W: 1.1 (ns)Castel ’99Castel ’99 1,938 M&W 1,938 M&W 12 y12 y 5th vs. 3rd quintile 5th vs. 3rd quintile M: 1.6 W: 1.1M: 1.6 W: 1.1Cordis ’00Cordis ’00 3,257 M3,257 M 8 y8 y >>90 vs. <70 bpm 90 vs. <70 bpm 2.02.0Reunanen ’00Reunanen ’00 10,717 M&W10,717 M&W 23 y 23 y M: 1.4 (>84 vs. <60)M: 1.4 (>84 vs. <60) W: 1.5 (>94 vs.<66)W: 1.5 (>94 vs.<66)Thomas ’01Thomas ’01 60,343 M HTN60,343 M HTN 14 y 14 y >80 vs. >80 vs. <<80 bpm80 bpm <55y:1.5 >55y:1.3<55y:1.5 >55y:1.3Matiss ’01Matiss ’01 2,533 M2,533 M 9 y9 y per 20 bpm: 1.5per 20 bpm: 1.5 >>90 vs. <60 bpm: 2.790 vs. <60 bpm: 2.7Ohasama ‘04 Ohasama ‘04 1,780 M&W 1,780 M&W 10 y 10 y M: 1.2 W: 1.1 (ns) per 5 bpmM: 1.2 W: 1.1 (ns) per 5 bpmOkamura ‘04 Okamura ‘04 8,800 M&W 8,800 M&W 16.5 y 16.5 y per 11 bpm (1 SD) M: 1.3 W: 1.2per 11 bpm (1 SD) M: 1.3 W: 1.2Jouven ’05Jouven ’05 5 713 M5 713 M 23 y 23 y SSudden death from AMI 3.92 (>75 bpm)udden death from AMI 3.92 (>75 bpm)

StudyStudy Population Follow-upPopulation Follow-up Cardiovascular mortality RR Cardiovascular mortality RR

Epidemiological studies on the relationship Epidemiological studies on the relationship between HR and CV mortality between HR and CV mortality (general population (general population

and HTN)and HTN)

Cliquez pour modifier le style du titre du masque

Cliquez pour modifier les styles du texte du masqueDeuxième niveau

Troisième niveau– Quatrième niveau

– Cinquième niveau

Resting heart rate and all-cause mortality Resting heart rate and all-cause mortality The Framingham StudyThe Framingham Study

Kannel WB et al Am Heart J. 1987;113:1489–1494.

Men, 35-64 years Men, 65-94 years

Heart Rate (bpm)

92-220

Mensink and Hoffmeister. Eur Heart J. 1997;18:1404-1410

Resting heart rate and all-cause mortality for Resting heart rate and all-cause mortality for 12 years in general population12 years in general population

<60 60-70 70-80 80-90 >90Heart rate (bpm)

Men (n=1798) Women (n=2908) Aged 40-80 Years

12123 French men

0.70.7

0.750.75

0.80.8

0.850.85

0.90.9

0.950.95

11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414 1515 1616 1717 1818 1919 2020 2121

HR<60 bpmHR<60 bpm 60 HR 8060 HR 80 80 HR 10080 HR 100 HR>100HR>100

Follow-up (y)

P=0.0001

Benetos, Hypertension. 33;44-52:1999

Resting heart rate and survival probability Resting heart rate and survival probability in in French general population (men)French general population (men)

High resting HR: an independent predictor of mortality in the Italian general population

Seccareccia F, et al. Am J Public Health. 2001;91:1258-1263.

High resting heart rate: an independent predictor of longer life in the elderly general population

Benetos A, et al. Am J Geriatr Soc. 2003;51:284-285.

Cohort study in 1407 men aged from 65 to 70 years, follow-up 18 years

HR: 66-73 bpm

HR: 60-65 bpm

HR: 78 bpm

HR: <60 bpm

High resting heart rate: an independent predictor of CV death in the Japanese general population

Okamura T, et al. Am Heart J. 2004;147:1024-1032.

Jouven et al. N Engl J Med. 2005;352:1951-1958

0.00.0

0.50.5

1.01.0

1.51.5

2.02.0

2.52.5

3.03.0

3.53.5

4.04.0

Relative riskRelative risk

Resting heart rate (bpm)Resting heart rate (bpm)

<60<60

286286 3333 1111

60-6460-64

191191

65-6965-69

229229 2121

70-7570-75

403403

>75>75

402402

Death from any causeDeath from any causeNon-sudden death from myocardial infarctionNon-sudden death from myocardial infarctionSudden death from myocardial infarctionSudden death from myocardial infarction

Resting heart rate and risk of mortality Resting heart rate and risk of mortality in general populationin general population

n=5713n=5713

High resting heart rate: a marker of high CV risk in the Norwegian middle-aged population

Aage T, et al. Eur Heart J. 2008;29:2772-2781.

The Paris Prospective Study, general population, 5 713 men; 23-years follow-up

Sudden death risk & Resting HR (general population)

Jouven X, et al., N Engl J Med. 2005;352:1951-1958.

0.00.0

0.50.5

1.01.0

1.51.5

2.02.0

2.52.5

3.03.0

3.53.5

4.04.0

Resting heart rate (bpm)<60 60-64 65-69 70-75 >75

P<0.001

2.5 times

Resting heart rate and cardiovascular Resting heart rate and cardiovascular deaths in in the type 2 diabetic patients deaths in in the type 2 diabetic patients

0022446688

101012121414161618182020

46-69 bpm46-69 bpm 70-75 bpm70-75 bpm 76-89 bpm76-89 bpm >90 bpm>90 bpm

Linnemann B, Janka BU, Exp Clin Endocrinol Diabetes 2003;111:215-222

Heart Rate as a Predictor of Hypertension

• A high heart rate has been shown to precede arterial stiffness¹ and also the development of hypertension upto 6 yrs later².

• The high heart rate is a reflection of underlying increased sympathetic nerve activity, both day and night³.

1.Franklin SS. Arterial Stiffness and hypertension. Hypertension 2005;45:349-51.2.Platini P, Dorigatti F, Zaetta V et al. Heart rate as a predictor of development of sustained hypertension in subjects screened for stage I hypertension: the HARVEST study. J Hypertens 2006;24:1873-80.3.Hering D et al. Resting sympathetic outflow does not predict the morning blood pressure surge in hypertension. J Hypertens 2011;29:2381-6.

Kolloch et al., Eur Heart J. 2008;29:1327-34.

INVEST study, 22 192 CAD patients; 2.7-year follow-up

Outcome (all-cause death, nonfatal MI, or nonfatal stroke)

Hazard ratio

Mean follow-up heart rate (bpm)

≤ 50

> 50 t

o ≤ 55

> 55 t

o < 60

> 60 t

o ≤ 65

> 65 t

o ≤ 70

> 80 t

o ≤ 85

> 85 t

o ≤ 90

> 70 t

o ≤ 75

> 75 t

o ≤ 80

> 90 t

o ≤ 9

> 95 t

o ≤ 1

ated hazard ratio

Spectrum of CHD

•Silent ischaemia•Stable Angina•Acute Coronary Syndrome (UAP,NSTEMI,STEMI)•Sudden Cardiac Death•Ischaemic Cardiomyopathy•Chronic Heart Failure

Evidences across Cardiovascular Continuum

Remodeling

Ventricular Dilation

Chronic Heart Failure

Myocardial Ischemia (angina)

AtherosclerosisLVH

Coronary Artery Disease

Coronary Thrombosis Arrhythmi

End-StageHeart Disease,Death

DyslipidemiaHypertensionDiabetesSmokingObesity

Myocardial Infarction

The Cardiovascular

Continuum

Dzau V et al. Circulation. 2006;114:2850-2870

Stable CAD & Normal EF

II. Role of heart rate

in development of atherosclerosis

Variation of coronary flow and shear stress during the cardiac cycle

10 mm Hg DIASTOLE120 mm Hg

Adapted from Giannoglou G et al. Int J Cardiol. 2008;126:302-312.

SYSTOLE

No flow (even retrograde subendocardial flow)

Coronary arterial flow (myocardial perfusion)

Increased shear stressLow and oscillatory shear stress

Coronary arteries are prone to atherosclerosis

High heart rate acceleratescoronary atherosclerosis progression

Average coronary Average coronary stenosis (%)stenosis (%)

Atherosclerotic area (mmAtherosclerotic area (mm22))

Beere PA, et al. Science. 1984;226:180-182.

6060P<0.02P<0.02 P<0.05P<0.05

High HRHigh HR Low HRLow HR00

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

Baboon

Cholesterol-rich diet

High HRHigh HR Low HRLow HR

Perski A, et al. Am Heart J. 1988;116:1369-1373.

Heart rate and coronary atherosclerosis

Minimum heart rate (bpm)

40 60 70 80 90

r= 0.70P<0.002

16 MI survivors, 6-month follow-up; 2 coronary angiographies; 24-hour ECG

III. Role of heart rate in

stable coronary artery disease

Heart rate & ischaemia

Resting Heart Rate and stable CHD

In 24913 patients with suspected or proven CHD, followed up for 15 yrs, a high resting HR > 83 bpm was predictive of total and cardiovascular mortality, with optimal survival at HR <62 bpm.

Diaz A et al. Eur Heart J 2005;26:967-74

HR <62 bpm

HR >78 bpm

Elevated Heart RateElevated Heart Rate

IschemiaIschemia Major CV eventsMajor CV events

Increased OIncreased O22 demand demandDecreased supplyDecreased supply

Progression of Progression of atherosclerosisatherosclerosis

PlaquePlaquerupturerupture

Short term Long term

Atherosclerosis

Vascular damageVascular damage

Role of elevated HR in the pathophysiology of CAD

Increased heart rate worsens ischaemia

Increased workload

Increased O2 demand

Decreased O2 supply

IschIschaaemiaemia

Decreased diastolic time

Increased heart rate

Heart rate is associated with increased risk of major Heart rate is associated with increased risk of major cardiovascular events in stable CAD eventscardiovascular events in stable CAD events

Rambihar S, et al. Circulation. 2010;122(suppl. 21): abstract12667

The ONTARGET/TRANSCEND trial (n=31531)

Cumulative incidence rates

Q4 71-78 bpmQ4 71-78 bpmQ5 Q5 >> 79 bpm 79 bpm

Q3 65-70 bpmQ3 65-70 bpmQ2 59-64 bpmQ2 59-64 bpmQ1 Q1 << 58 bpm 58 bpm

Years of follow-up0 1 2 3 4 5

Heart rate as a major determinant of ischemia

1. Andrews TC et al. Circulation.1993;88:90-100.

2020%%

<60<60 60-6960-69 70-79 80-89 70-79 80-89 >89>89

Heart rate at rest, bpmHeart rate at rest, bpm

XX 2 2 timestimes

Heart Rate as a predictor of coronary events

Aronov W. S et al. Am J Cardiol. 1996;78:1175-1176

New coronary New coronary events, % events, %

<60<60 61-7061-70 71-8071-80 81-9081-90 91-10091-100 >100>10000

7070 XX 2 2 timestimes

Mean heart rate on 24-Hour Ambulatory ECG, bpm

N= 1 311 CHD patients with 48-months follow-up

P<0.0001

5 bpm of HR = 1.14 incidence of coronary events

Increased heart rate worsens ischaemia

Increased workload

Increased O2 demand

Decreased O2 supply

IschIschaaemiaemia

Decreased diastolic time

Increased heart rate

Lowering heart rate relieves ischaemia

Decreased workload

Decreased O2 demand

Preserved O2 supply

IschIschaaemiaemia

Increased diastolic time

Decreased heart rate

Angina Severity and Mortality

Spertus JA, et al. Circulation. 2002;106:43-9

SAQ=Seattle Angina Questionnaire

39% of patients receiving β-blockers had a heart rate above 70 bpm

Patients (%) in different HR according to HR lowering treatment at baseline (n=2 005) from The Euro Heart Survey

Inadequate control of heart ratein patients with stable angina

≤≤6262 63-7063-70 71-7671-76 77-8277-82

CCBsCCBs

BBsBBs

Resting HR (bpm)Resting HR (bpm)≥≥8383

Daly C et al. Daly C et al. Postgrad Med J Postgrad Med J 2010;86:212-217.2010;86:212-217.

A Diaz et al. EHJ 2005; 26: 976-74

IV. Role of heart rate in

acute coronary syndrome

Resting Heart Rate and ACS

In 139194 patients with NSTE-ACS, there was J-shaped relationship between the resting HR and all-cause mortality, with HR < 50 bpm being associated with increased mortality ( whether or not a b blocker was present).

Bangalore S et al. Eur Heart J 2010;31:552-60

High Heart Rates are Predictive of Coronary Plaque Ruptures

Heidland UE, Strauer BE. Circulation. 2001;104:1477-1482. AS-ct11-0706

Higher heart rate on admission increases risk of mortality in patients with acute MI

Hjalmarson A, et al. Am J Cardiol. 1990;65:547-553.

• n = 1,807 AMI

• multi-centre

• mortality: in-hospital & post discharge

• with / without heart failure

HR<96 HR<96 96-12 113-133 96-12 113-133 >133 >133

Death/MI at 30 daysDeath/MI at 30 days

Death/MI at 1 yearDeath/MI at 1 year

Age (years)Age (years)

Heart rate (bpm)Heart rate (bpm)

<70 <70 0 0

70–89 70–89 77

90–109 90–109 13 13

110–149 110–149 2323

150–199 150–199 36 36

>200 >200 4646

Systolic BP (mmHg)Systolic BP (mmHg)

Creatinine (mg/dL)Creatinine (mg/dL)

Killip classKillip class

Cardiac arrest at Cardiac arrest at admission Elevated admission Elevated cardiac markers ST-cardiac markers ST-segment deviationsegment deviation

GRACE scoreGRACE score for risk prediction in patients with ACS for risk prediction in patients with ACS

Goncalves P. European Heart Journal (2005) 26, 865–872

GRACE Heart rate

V. Role of heart rate in

Postmyocardial infarction

All cause mortality

Sudden cardiac death

HR variability

HRmean

Sensitivity

Copie X, et al JACC 1996;27:270-6.

• n = 579

• Heart rate and LVEF at discharge

• 2-year follow-up

• HR better predictor of mortality than LVEF

Heart rate better predictor of post-MI mortality than LVEF

In predischarge patients with MI, both 24 hr mean HR and HR variability were predictors of mortality over next 2 yrs.

Kjekshus JK. Eur Heart J. 1985;6:A29. Am J Cardiol 1986;57:43F

Early interventionAMI size r=0.97

Post AMIMortality r=0.79Reinfarction r=0.59

R=0.79P<0.005

Reduction of heart rate prolongs life post MI

In postmyocardial infarction period, survival was closely related to the reduction of HR on b-blockers.

PropranololAtenolol

Timolol

Metoprolol

Propranolol

-4 -8 -12 -16 -20

Reduction in heart rate (min-1)

Reduction ininfarct size (%)

Kjekshus JK. Am J Cardiol. 1986;57:43F-49F.

Lowering heart rate reduces infarct size in MI

Heart rate at discharge & 6-month

mortality (GISSI-3)

Zuanetti et al. Eur Heart J. Supplements 1999, Vol. 1 (Suppl H):H52-H57

<60 bpm 60-80 bpm60-80 bpm 81-100 bpm81-100 bpm >100 bpm

1.91.93.93.9

9.39.3

20.220.2

2020 n=11020

6-month mortality

10 times

HR loweringHR lowering & reduction in & reduction in cardiac deathscardiac deaths (post-MI patients)(post-MI patients)

Cucherat M et al. Eur Heart J. 2006, 27(Abstract Suppl):590.

10 bpm HR reduction = 10 bpm HR reduction = -- 2626% cardiac death% cardiac death

Meta-regression of 12 controlled studiesMeta-regression of 12 controlled studies

HR HR (bpm)(bpm)

-5 -10 -15 -200

P<0.001P<0.001

VI. High resting heart rate

in chronic heart failure

HR and one-year mortality in CIBIS-II trial

Lechat P, et al. Circulation. 2001;13:1428-33.

High heart rate is deleterious in clinical heart failure

One-year mortality (%)

84 > 84 Heart rate (bpm)

High resting heart rate is an independent predictor of death in patients with heart failure

Lechat P. CIBIS II. Circulation. 2001:103:1428-1433.

Trials that shows heart rate lowering reduces mortality in CHF

-18 -16 -14 -12 -10 -8 -6 -4 -2 0 2 4 6 8 10

XAMOTEROLPROFILE

PROMISE

VHeFT(HDZ/ISDN)SOLVD

CONSENSUS

VHeFT(prazosin)

US CARVEDILOL

BHATCIBIS

NORTIMOLOL

GESICA

Change in mortality (%)

Change in heart rate (bpm)Kjekshus et al. Eur Heart J. 1999 (suppl), H64-H69

CHARM program: baseline heart rate & outcome

Castagno D. J Am Coll Cardiol. 2012;:59. 2012:1785–95

Resting heart rate predicts outcomes in heart failure, regardless of LVEF or beta-blocker use

Heart rate tertile

T1 mean 60

T2 mean 72

T3 mean 86

American College of Cardiology / American Heart Association

ACC/AHA guidelines. 2002.

Lowering heart rate???new treatment option

A key objective to save livesin both CAD & heart failure

With WHAT & HOW we should lower it?

Heart rate lowering with Heart rate lowering with beta-blockersbeta-blockers

& & Calcium channel blockersCalcium channel blockers

PlaceboPlaceboPropranololPropranolol DiltiazemDiltiazem22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424

Mean Heart Rate (bpm)Mean Heart Rate (bpm)

xxxx xx

xx xxxx xx

Daily frequency of ischemic episodesDaily frequency of ischemic episodes

Stone PH, Circulation 1990;82:1962-1972

Sir James BlackBritish pharmacologist

Discovered propranolol in 1960

and brings wonderful benefits to

coronary patients

Earned Noble Prize in 1980

Passed away in 2010 at the age of

Effects of beta-blockers

= Reduces heart rate

= Reduces LV contraction

= Reduces conduction

= Reduces blood pressure

= Prevents coronary vasodilatation during exercise

Limitation of BETA-BLOCKERSLimitation of BETA-BLOCKERSHard to reach target doseHard to reach target dose

Hypertriglyceridemia

Atrio-ventricular block 2 and 3

Decreased HDL cholesterol

Sexual dysfunction

Fatigue

Insomnia

Asthma

Diabetes

Rebound effect

Are there anything more than beta-blockers?

Lowering heart rate???new treatment option

A key objective to save livesin both CAD & heart failure

with Ivabradine:

Pure heart rate reduction

Preserves blood pressure, myocardial

contractility and coronary vasodilatation

Major antianginal efficacy

Reduces CV events (BEAUTIFUL)

Additive efficacy with beta-blockers

Dosage: 5mg BD to 7.5mg BD

The first selective and specific If inhibitor

Ivabradine

Ivabradine: pure heart rate reduction

If inhibition reduces the diastolic depolarization slope and thereby lowers heart rate

Pureheart ratereduction

-40 mV

-70 mV

Thollon C, et al. Brit J Pharmacol. 1994;112:37-42.

closedopen

closed

Ivabradine

• If current is an inward Na+/K+ current that activates pacemaker cells of the SA node

• Ivabradine– Selectively blocks If in a current-

dependent fashion– Reduces slope of diastolic

depolarization, slowing HR

Ivabradine (mg)

5 bid 7.5 bid

Atenolol (mg)

50 od 100 odn=286n=595 n=300

Heart rate reduction

Ivabradine vs Atenolol

Tardif JC, et al. Eur Heart J. 2005;26:2529-2536.

-15 bpm -16 bpm

40 50 60 70 80 90 100 110 120

Baseline HR (bpm)

5 mg bid

7.5 mg bid

Heart Rate Reduction by Ivabradine is Dependent on Baseline Heart Rate

(n=720): Safety Relevance!

Anti-ischemic efficacy of Ivabradine

compared to beta blockers

INITIATIVE

25 mg od

placebo

ate 50 mg od(n=307)

iva 5 mg bid (n=315)

iva 5 mg bid (n=317)

placebo

50 mg od

placebo

Atenolol 100 mg od

Ivabradine 7.5 mg bid

Ivabradine 10 mg bid

M1 ETT

Randomization(n=939)

M4 ETT

Wash-out2-7 days

Run-in7 days

Run-out14 days1 month 3 months

Pre-selection(n=1789)

The INITIATIVE study

Mo ETT

Tardif J-C, et al. Eur Heart J. 2005;26:2529-2536.

The clinical efficacy of Ivabradine Vs beta-blockers

INITIATIVE

AAtenololtenolol 100 mg 100 mg

Reduction in number of angina attacks Reduction in number of angina attacks (after 4-month treatment)(after 4-month treatment)

Antianginal efficacy of Ivabradine

Ivabradine Ivabradine 7.5 mg7.5 mg

Number/weekNumber/week

- 70%- 72%

INITIATIVE

Tardif JC. Drugs of Today. 2008;44:171-181.

Increase in exercise capacity (total exercise duration) related to 1 beat of heart rate reduction

Change in TED (sec) at 4 months per 1 beat of HR reduction

Ivabradine 7.5 mg

Preserved exercise-induced coronary vasodilation? Reduced coronary vasomotor tone? Prolonged diastolic duration and myocardial perfusion?Lack of negative inotropic effect? Lack of lower limb arterial vasoconstriction

INITIATIVE

Efficiency of exclusive heart rate reduction

Atenolol 100 mg od better Ivabradine 7.5 mg bid better

0- 35 sec +35 sec

Total exercise duration

Time to limiting angina

Time to angina onset

Time to 1-mm ST-segmentdepression

ETT parameters at trough of drug activity after 4 months

Equivalence limits

P<0.0001

P for non-inferiority

P<0.0001

Clinical Efficacy of ivabradine versus atenolol in the INITIATIVE study

INITIATIVE

INITIATIVE Key messages

1. Ivabradine is as effective as Atenolol 100 mg

2. For 1 beat of HR reduction, Ivabradine provides 2

times > exercise capacity than Atenolol (because of its

pure heart rate reduction preserving contractility, coronary

vasodilation, BP)

INITIATIVE

Anti-ischemic efficacy of Ivabradine in

patients already treated with beta

blockers(1 Tardif JC, Ponikowski P, Kahan T; ASSOCIATE study investigators. Efficacy of the If current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4 month, randomized, placebo-controlled trial. Eur Heart J. 2009;30:540-548

Main inclusion criteria

• Patients with documented CAD with a history of chronic

stable angina

• Already on atenolol 50mg od or other BB (equivalent dosage)

• HR>60bpm

• Positive exercise tolerance test

(1 Tardif JC, Ponikowski P, Kahan T; ASSOCIATE study investigators. Efficacy of the If current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4 month, randomized, placebo-controlled trial. Eur Heart J. 2009;30:540-548

Ivabradine reduces heart rate in patients already receiving β-blockers

Baseline M2 M4

IvabradineIvabradine 5 mg bid5 mg bid

Ivabradine 7.5 mg bid (90% of pts)

60 (- 7 bpm)

- 9 bpm

Ivabradine + atenolol

Placebo + atenolol

IvabradineIvabradine7.5 mg bid 7.5 mg bid

Heart rate (bpm)

Ivabradine + atenolol

Placebo + atenolol

Total exercise duration

Time to limiting angina

Time to angina onset

Time to 1mm ST depression

P<0.001 P<0.001

Ivabradine increases all ETT parameters in patients already receiving BBs

Change in ETT criteria* (s) at 4 months

+ 3 times

“This study represents the most compelling single demonstration of the benefit of any combination of antianginal drugs published to date” Eur Heart journal

Tardif JC, et al. Eur Heart J. 2010;31(suppl. 1):198 (abstract 1335).

Ivabradine PlaceboPlacebo

Asymptomatic 3.0%3.0% 0.5%0.5%

Symptomatic 1.1%1.1% 0.3%0.3%

Safety of ivabradine in combination

with beta-blocker

Bradycardia

Withdrawal due to sinus bradycardia 0.9%0.9% 0%0%

Key messages

• First compelling benefits of improvements in exercise parameters in combination with beta-blockers

• Safe in combination with beta-blockers

•Reinforces Ivabradine’s baseline dependent HR reduction (Baseline HR: 67 bpm, drop by 9)

•From 60 bpm, all CAD patients receving Ivabradine should be up-titrated to 7.5 mg (87% pts = 7.5 mg)

In combination with BBs, Ivabradine provides the best benefits compared to other antianginals

Tardif JC, et al. Eur Heart J. 2008;29(suppl):386 (abstract 2380). Klein meta-analysis - CARISA

+ Ivabradine*+ Ivabradine*

Change of time to 1- mm ST depression - mean difference from placebo (s)

0 10 20 30 40

P<0.001

b-blockers

+ Calcium + Calcium antagonists**antagonists** P=0.21

+ Ranolazine**+ Ranolazine** P=NS

+ Nicorandil or + Nicorandil or molsidomine or molsidomine or

L-A nitratesL-A nitratesNo dataNo data

At trough of drug activity

*Standard Bruce Protocol

**Modified Bruce

-60-50-40-30-20-10

Previou

s PTCA*

Previou

s CABG*

Diabete

Asthma/C

Age >6

Antianginal efficacy of ivabradine across all subpopulations of angina patients

Tendera M, et al. Cardiology. 2009;114:116-125.

5 randomized trials including 24 25 stable angina pts

51% to 70% reductions in frequency of Angina Attacks

Change in angina attacks from baseline (%)

Does It Work in Clinical Practice?Does It Work in Clinical Practice?ADDITIONSADDITIONS STUDYSTUDY

• 2,230 2,230 Stable Stable angina angina patients, HR patients, HR > 60 bpm> 60 bpm•Insufficiently controlled with BB aloneInsufficiently controlled with BB alone•Change in medical treatment (intolerance or insuf efficacy)Change in medical treatment (intolerance or insuf efficacy)

• On top of On top of BBBB• 4 months 4 months treatmenttreatment• Parameters recordedParameters recorded

1.Heart Rate 2.Angina attacks 3.Nitrate consumption4.Tolerance5.QOL

Design of addition studyDesign of addition study

Werdan K, et al. Clin Res Cardiol. 2012.

Multicenter, prospective study in 2330 patients with stable angina pectoris

Angina attacks

0.6 0.3

Baseline 1 Month 4 Months

P<0.001 for all differences

Short-acting nitrates

0.80.4

Baseline 1 Month 4 Months

P<0.001 for all differences

Ivabradine in combination with beta-blockers Ivabradine in combination with beta-blockers improves symptoms in angina patients improves symptoms in angina patients

Effect of Ivabradine on

Morbi-mortality in CAD

Angina

Evidences of Ivabradine

MorBidity-mortality EvAlUation of The I f inhibitor

ivabradine in patients with coronary disease and

left ventricULar dysfunction

Primary objective

1. Effects of Ivabradine on the prevention of cardiovascular

events in patients with CAD and LV systolic dysfunction

2. To examine the effects of elevated HR (≥ 70 bpm) in patients

with CAD and LV systolic dysfunction on cardiovascular events

Inclusion criteria

• Documented coronary artery disease

• Documented LV systolic dysfunction (EF < 40%)

• Sinus rhythm and resting heart rate ≥ 60 bpm

K. Fox et al. Am Heart J. 2006;152:860-866

Study design

Visits

3 YEARS

K. Fox et al. Am Heart J. 2006;152:860-866

Ivabradine 5 mg 7.5 mg bid

placebo

On top of recommended therapy

Values in parentheses are standard deviations

PlaceboPlacebo ivabraineivabraine

Male, % Male, % 8383 8383 8383

Age, years Age, years 65.0 (8.4)65.0 (8.4) 65.3 (8.5)65.3 (8.5) 65.2 (8.5)65.2 (8.5)

NumberNumber 54385438 54795479 10 91710 917

Resting heart rate, bpmResting heart rate, bpm 71.6 (9.9)71.6 (9.9) 71.5 (9.8)71.5 (9.8) 71.6 (9.9)71.6 (9.9)

Systolic BP, mm HgSystolic BP, mm Hg 127.9 (15.5)127.9 (15.5) 128.1 (15.7)128.1 (15.7) 128.0 (15.6)128.0 (15.6)

Diastolic BP, mm HgDiastolic BP, mm Hg 77.5 (9.2)77.5 (9.2) 77.4 (9.3)77.4 (9.3) 77.5 (9.3)77.5 (9.3)

AllAll

LV ejection fraction, %LV ejection fraction, % 32.3 (5.5)32.3 (5.5) 32.4 (5.5)32.4 (5.5) 32.4 (5.5)32.4 (5.5)

Lancet, online August 31 2008

Baseline characteristics

Optimal preventive therapyOptimal preventive therapy

Study Therapy Aspirin orantithrombotic

Statins

RASagents

TRACE 1995 AMI + LVD Trandolapril 92 – 17

CIBIS II 1999 CHF Bisoprolol 40 – 96

MERIT HF 1999 CHF Metoprolol 46 25 89

HOPE 2000 High CV risk Ramipril 75 28 39

COPERNICUS 2001 CHF Carvedilol – – 97

CAPRICORN 2001 AMI + LVD Carvedilol 86 – 98

EUROPA 2003 Stable CAD Perindopril 92 58 62

COMET 2003 CHF Metoprolol/carvedilol 35 20 92

SENIORS 2005 Elderly CHF Nebivolol 43 20 82

COURAGE 2007 Stable CAD Optimal medical therapyRevascularization

95 89 89 65

REACH CAD Registry 93 76 62 8BEAUTIFUL 2008 CAD + LVD ivabradine 94 74 87 90

Patients

Mean HR reduction in overall population

Heart rate (bpm)

Follow-up (days)0 15 30 90 180 360 540 720

Placebo

Ivabradine

-5 bpm

HR as inclusionHR as inclusion ≥ 60 bpm Average Average 71 bpm71 bpm

Mean HR reduction(Patients with baseline HR ≥ 70 bpm)

Heart rate (bpm)

Follow-up (days)

0 15 30 90 180 360 540 720

Placebo

Ivabradine

Mean dose of Ivabradine 6.64 mg bid

-7 bpm

Effect of ivabradine on the primary endpoint (overall population)

Effect of ivabradine on the primarycomposite endpoint (HR ≥ 70 bpm)

Effect of ivabradine in patients with HR ≥70 bpm

coronary revascularization

hospitalization for MI

Heart rate as a predictor of

CARDIOVASCULAR DEATH

Fox et al. Lancet. 2008;372:817-21.

REVASCULARIZATION

HOSPITALIZATION FOR HF

HOSPITALIZATION FOR MI

0.11431%0.69Fatal MI

0.02322%0.78Fatal and nonfatal MI or unstable angina

0.01630%0.70Coronary revascularization

0.00923%0.77Fatal and nonfatal MI, unstable anginaor revascularization

0.00136%0.64Fatal and nonfatal MI

P valueRiskreduction

Hazardratio

Predefined end point

Ivabradine reduces coronary risk in stable coronary patients with HR ≥ 70 bpm

Fox et al .Lancet. 2008;372:807-816.

Secondary prevention of myocardial Secondary prevention of myocardial infarction in stable CAD infarction in stable CAD

Number needed to treat to prevent one event per 1 year (NNT-1) Study Event

ACE inhibitorsACE inhibitors

Statins Statins

Ivabradine

Scandinavian Simvastatin Survival Study (4S)1

63 patientsMajor coronary event (coronary death and non-fatal MI)

HOPE2 229 patientsFatal and non-fatal MI

BEAUTIFUL study3 93 patientsFatal and non-fatal MI

1- Kjekshus J. Am J Cardiol.1995;76:64C-68C. 2-HOPE Investigators N Eng J Med. 2000;342:145-1533- Fox K, et al. Lancet. 2008;372:807-816.

RanolazineRanolazine

TrimetazidineTrimetazidine

-Blockers-Blockers

Calcium antag.Calcium antag.

NitratesNitrates

NicorandilNicorandil

Ivabradine

Improvedtime to onset

of ST-segmentdepression

Decreasein anginalepisodes

Improvedtotal

exerciseduration

Reducedrevascularization

NANA––

––++

––

Preventionof MI

NANA––

––––––

––

Improvedsurvival

NANA––

––––––

––––

Ivabradine - the only antianginal treatment to reduce myocardial infarction in stable coronary patients

Fox K, et al. Lancet. 2008;372:807-816

Adapted from ESC Guidelines on stable angina 2006

New evidence from

ESC’09

Breaking

A subgroup analysis in patients with limiting anginalimiting angina

at baseline

AnginaAngina

Patients with angina and follow-up

1507 randomizedwith angina

734 to Ivabradine 773 to placebo

773 analyzed734 analyzed

12 138 screened

10 917 randomized

Angina

In patients with angina as limiting symptoms at entry, ivabradine independently

improved the primary composite endpoint

reduced hospitalization for fatal and non-fatal MI

Angina substudy resultsAngina

Ivabradine reduces primary composite end point

HR (95% CI), 0.76 (0.58–1.00), P=0.05

HR (95% CI), 0.69 (0.47–1.01), P=0.06

0.5 1 1.5 20

0.5 1 1.5 2

Placebo

Ivabradine

Placebo

Ivabradine

*Cardiovascular mortality or hospitalization for fatal and nonfatal MI or HF Fox K, et al. Eur Heart J. 2009; 30:2337-2345 .

Event rate (%) Event rate (%)

-24% -31%

All patients with limiting angina Patients with limiting angina & HR > 70 bpm

Placebo

Ivabradine

HR (95% CI), 0.27 (0.11–0.66),P=0.002

Placebo

Ivabradine

HR (95% CI), 0.58 (0.37–0.92),P=0.021

0.5 1 1.5 20

0.5 1 1.5 2

Ivabradine reduces hospitalization for MI

* Fatal and nonfatal eventsFox K, et al. Eur Heart J. 2009; 30:2337-2345 .

Event rate (%) Event rate (%)

- 42% -73%

Angina

All patients with limiting angina Patients with limiting angina & HR > 70 bpm

BradycardiaHypotensionNegative inotropic effectPeripheral vasoconstrictionIncrease coronary resistanceBronchospasmDecrease to insuline responseFatigueDepressionSleep disturbancesErectile dysfunctionLower limbs oedemaConstipationVisual effects

xxx xxxxxxxx

BB CCB Ivabradine

Ivabradine free from the side-effects of the -blockers and Calcium-channel-blockers

In Angina patients, Ivabradine reduces

hospitalization for fatal and non-fatal MI by - 42%

- 73% in patients HR > 70 bpm

Fox K, et al. Cardiology. 2008;110:271-282.

CAD patients with heart rate >70 BPM has higher risk of

CV mortality by +34%hospitalization for HF by +53%

hospitalization for MI by +46% (compared to HR < 70 BPM)

SUMMARY

In CAD patients with LVD, a HR of ≥ 70 bpm predicts an

adverse outcome for CV death, hospitalization for HF or

MI and revascularization

Key Messages

Ivabradine is well tolerated (2.7% symptomatic bradycardia and 0.5% visual symptoms)

Ivabradine ( HR 7 bpm) improves coronary outcomes in

patients with HR ≥70 bpm

Effect of Ivabradine on

Morbi-mortality in AMI

Systolic Heart failure treatment withthe If inhibitor ivabradine Trial

Primary objective

To evaluate whether the To evaluate whether the IIff inhibitor ivabradine inhibitor ivabradine

improves improves cardiovascular outcomescardiovascular outcomes

in patients with in patients with moderate to severemoderate to severe chronic heart failure chronic heart failure

(LVEF (LVEF 35%) 35%) & & Heart rate Heart rate 70 bpm70 bpm, ,

on top of best recommended therapyon top of best recommended therapy

EUROPEGermany Portugal

Belgium Greece SpainDenmark Ireland SwedenFinland Italy TurkeyFrance The Netherlands UK

BulgariaCzech RepublicEstoniaHungary

South AmericaArgentinaBrazilChili

North AmericaCanada

ASIAChinaHong KongIndiaSouth KoreaMalaysia

Australia

LatviaLithuaniaNorwayPolandRomania

RussiaSlovakiaSloveniaUkraine

The largest Heart Failure trial

6505 patients, 37 6505 patients, 37 countriescountries, 677 , 677 centrescentres

ASIA : 520 pts

18 years

NYHA Class II to IV heart failure (ischemic or non-ischemic)

LV systolic dysfunction (EF 35%)

Heart rate 70 bpm with sinus rhythm

Documented hospital admission for worsening heart failure 12

months

Inclusion criteria

Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.

Study endpoints

Cardiovascular death Hospitalization for worsening heart failure

Primary composite endpoint

Other endpoints All-cause / CV / HF death All-cause / CV / HF hospitalization Composite of CV death, hospitalization for HF or non-fatal MI NYHA class / Patient & Physician Global Assessment

In total population and in patients with at least 50% target dose of beta-blockers In total population and in patients with at least 50% target dose of beta-blockers

Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.

Baseline characteristics

IvabradineIvabradine32413241

PlaceboPlacebo32643264

Mean age, yMean age, y 60.760.7 60.160.1 Male, %Male, % 7676 7777 Ischaemic aetiology, %Ischaemic aetiology, % 6868 6767 NYHA II, %NYHA II, % 4949 4949 NYHA III/IV, %NYHA III/IV, % 5151 5151 Previous MI, %Previous MI, % 5656 5656 Diabetes, %Diabetes, % 3030 3131 Hypertension, %Hypertension, % 6767 6666

Swedberg K, et al. Lancet. 2010;online August 29.

Mean heart rate reduction

70% of patients70% of patients on ivabradine 7.5 mg bid on ivabradine 7.5 mg bid

0 2 weeks 1 4 8 12 16 20 24 28 32MonthsMonths

Heart rate (bpm)Heart rate (bpm)

Placebo

Ivabradine

Swedberg K, et al. Lancet. 2010;online August 29.

- 8 bpm

0 6 12 18 24 30

Primary composite endpoint (CV death or hospital admission for worsening HF)

Cumulative frequency (%)Cumulative frequency (%)

Placebo

Ivabradine

HR = 0.82 (0.75–0.90) P < 0.0001

Swedberg K, et al. Lancet. 2010;online August 29.MonthsMonths

0 6 12 18 24 30

Hospitalization for HF

- 26%Placebo

Ivabradine

HR = 0.74 (0.66–0.83)P < 0.0001

Death from heart failure

0 6 12 18 24 30

HR = 0.74 (0.58–0.94) P = 0.014

Placebo

Ivabradine

0 6 12 18 24 30

Cardiovascular death

Placebo

Ivabradine

HR = 0.91 (0.80–1.03)P = 0.128

90 % of pts on BB and annual event rate in placebo is low (13%) ??

Baseline heart rate is a predictor of endpoints on placebo

Primary composite endpoint: risk increases by 2.9% per 1-bpm increase, and by 15.6% per 5-bpm increase

00 6 12 18 24 30 Months

≥87 bpm

80 to <87 bpm

75 to <80 bpm

72 to <75 bpm70 to <72 bpm

P<0.001

Patients with primary composite endpoint (%)

Böhm et al, Lancet 2010; 376: 886-894.

Prospective Study

Baseline heart rate is a predictor of endpoints on placebo

00 6 12 18 24 30

Months

≥87 bpm

80 to <87 bpm

75 to <80 bpm

72 to <75 bpm

70 to <72 bpm

P<0.001

Hospital admission for heart failure (%)

≥87 bpm

80 to <87 bpm

75 to <80 bpm72 to <75 bpm70 to <72 bpm

00 6 12 18 24 30

Months

Cardiovascular death (%)

P<0.001

Böhm et al, Lancet 2010; 376: 886-894.

Benefit of ivabradine in all prespecified subgroups

Patients with an adverse event, leading to withdrawal

Ivabradine N=3232, n (%)

Placebo N=3260, n (%)

p value

All adverse events 467 (14%) 416 (13%) 0.051

Symptomatic bradycardia 20 (1%) 5 (<1%) 0.002

Asymptomatic Bradycardia 28 (1%) 5 (<1%) <0.0001

Atrial fibrillation 135 (4%) 113 (3%) 0.137

Phosphenes 7 (<1%) 3 (<1%) 0.224

Blurred vision 1 (<1%) 1 (<1%) 1.000

Treatment discontinuation

Swedberg K, et al. Lancet. 2010; online August 29.

Inger ekman et al. European Heart Journal: August 29 2011

Ivabradine improves HQoL in HF patients

Sub-group analysis from SHIFT

Assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ)

1944 patients (968 ivabradine, 976 placebo)

Ivabradine increases LVEF

European Heart Journal doi:10.1093/eurheartj/ehr311

ACEI+BB+MR antagonist+ Ivabradine

ACEI+BB+MR antagonist

Sub-group analysis from SHIFT

411 patients (ivabradine 208, placebo 203), assessed at baseline & 8 months

Conclusion

• HF with with systolic dysfunctionsystolic dysfunction and elevated HR is associated

with poor outcomes (PCE in the placebo group is 18%/year)

• Ivabradine reduced CV mortality or HF hospitalization by -18%

• Mainly driven by effect on HF death & hospitalization by - 26%

• Ivabradine was safe and well tolerated

Morbidity benefit of Ivabradine in Heart Failure

compared to beta blockers

CARVIVA HF

CARVIVA HF: prospective, randomised, open study N=123 pts, compare effects on exercise capacity and QoL with carvedilol, ivabradine, or combination

Ivabradine, up to 7.5 mg bid N=42

Carvedilol, up to 25 mg bid N=39

Carvediolol/ivabradine, up to 12.5/5 mg bid N=42

ScreeningBaseline

Randomisation

End of study

-8 -1 0 12Time (weeks)2

End of uptitration

optimize ACEI,

washout any β-blocker

Volterrani et al. Int. J. Cardiol. 2011;151:218-224

3 months

CARVIVA primary endpoint: Change in CARVIVA primary endpoint: Change in exercise capacityexercise capacity

*P<0.01 vs baseline. †P<0.01, ††P<0.02 vs carvediolol

*†† *††

Volterrani et al. Int. J. Cardiol. 2011;151:218-224

Bagriy AE, Shchukina EV, Malovichko SI, Prikolota AV. Addition of Ivabradine to Carvedilol Reduces Duration of Carvedilol Uptitration and Improves Exercise Capacity in Patients with Chronic Heart Failure. J Am Coll Cardiol. 2013;61(10_S). doi:10.1016/S0735-1097(13)60700-7.

Ivabradine increases exercise capacity

• 41 patients in sinus rhythm with previous MI• CHF (NYHA class II-III), and HR ≥70 bpm.

Carvedilol up to 25 mg bid + Ivabradine 7.5 mg BD

Carvedilol up to 25 mg bid

Morbidity benefit of Ivabradine in Heart

Failure on top of optimal treatment

The INTENSIFY study: practical daily The INTENSIFY study: practical daily effectiveness and tolerance of ivabradine in effectiveness and tolerance of ivabradine in chronic systolic heart failure in Germanychronic systolic heart failure in Germany

Zugck C, Martinka P, Stöckl G. Ivabradine treatment in a chronic heart failure patient cohort: symptom reduction and improvement in quality of life in clinical practice. Adv Ther. 2014;31:961-974.

RESULTSRESULTS

Ivabradine rapidly improves symptoms

+Ivabradine +Ivabradine

Ivabradine reduces heart failure symptoms

Zugck C et al. Ivabradine treatment is effective in chronic systolic heart failure in clinical practice irrespective of left ventricular ejection fraction at baseline. ClinRes Cardiol. 2014;103(Suppl 1):P1456.

IMPACT ON CLINICAL PRACTICEIMPACT ON CLINICAL PRACTICE

The INTENSIFY study has shown that there is room for further symptomatic improvement in chronic heart failure patients, despite current treatments such as beta-blockers.

Ivabradine has proven in clinical practice to be rapidly effective in reducing symptoms of heart failure, and improving quality of life in chronic heart failure patients.

Deschaseaux C et al. Efficacy of heart failure pharmacological treatment classes and combinations: network meta-analyses. Eur J Heart Fail. Abstracts Supplement.

2014;16(Suppl 2):161.

Efficacy of heart failure pharmacological treatment classes and combinations: Network meta-analysis

All-cause mortality rate per 100 person-years

Effect of Ivabradine on Morbi-mortality in

CAD with normal LV function

Ivabradine Starting dose 7.5 mg bid

Placebo bid

Run in2 - 4 weeks

M006M003M000 Every 6 months

Target HR: 55-60 bpm

MethodsEvents: 4.5% per year in the placebo group 1070 primary composite endpoints (cardiovascular death and non fatal MI N = 11 330, mean follow up = 2.5 years; RRR = 18%, α bilateral 5%, power 90%

PopulationOutpatients with stable CAD without LVSD (EF > 40%) or clinical signs of HF, with appropriate CV medication

95% CI [-10.0; -9.5]

9.7 bpm

ConsiderationsFirst: the dosage

• Higher dosages : Starting at 7.5 mg BD and uptitrated to 10 mg BD if heart rate >60 bpm

• 51% patients received 10 mg BD 27% patients 7.5 mg BD and 22% patients 5 mg BD

• Incidence of bradycardia in SIGNIFY was 17.9% Vs. 4.6% in BEAUTIFUL

• In SIGNIFY, 1135 patients received verapamil or diltiazem and 262 received stronger inhibitors of CYP 3A4

• Those receiving verapamil, diltiazem or strong CYP 3A4 inhibitors on top of Ivabradine had a 61% increase in primary end point and 93% increase in nonfatal MI

• After excluding these patients, the risk versus placebo decreased

Considerations 2: Concomitant use of diltiazem, verapamil or CYP 3A4

inhibitors

Considerations 2: Concomitant use of diltiazem, verapamil or CYP 3A4

inhibitors

• Ivabradine is metabolized via CYP 3A4

• Diltiazem and Verapamil mildly inhibit CYP 3A4 and increase exposure to ivabradine, in addition to lowering heart rate

• Ketoconazole or macrolide antibiotics are stronger inhibitors of CYP 3A4, and increase exposure to Ivabradine 7-8 fold

Morbi-mortality benefit ofheart rate lowering depends on LV function

Conclusion of

•It shows that HR reduction in CAD without HF is advantageous for symptoms relief, but does not improve outcomes.

• Ivabradine should not be used in combination with Verapamil, Diltiazem, or ketoconazole, or macrolide antibiotics.

• Ivabradine should be used at the usual dose of 5 mg BD uptitrated to 7.5 mg BD in order to avoid excessive bradycardia.

Case example in CCU MGH•60 yr male, ex-smoker, hypertension, stable angina since 2015.on ASA, Clopidogrel, Meroprolol, Nicorandil, Atorvastatin, Perindopril

12.8.2015

Oct 2015-Angina not improved- advised for revascularization- declined

5 pm,8.5 2016- Severe angina, BP-80/60admitted to CCU MGH

Omit BB, ACEIIV Doubtamine

8 am, 9.5 2016- Still angina, BP-110/70, orthopnoeic, pul oedema

IV DoubtamineIV GTNIV Lasix

11.5 2016- free of angina, BP-120/70, can lie in flat

Added Ivabradine 5mg BDUptitrated to 7.5mg BD next day

14.5 2016- free of angina, BP-120/70, oral Lasix, awaiting for angio

CONCLUSION

• High resting heart rate is a predictor of mortality in a large variety of populations:

• General population• Prehypertensive patients• Hypertensive patients • Stable CAD patients• ACS patients• Post-MI patients • Heart failure patients

Ivabradine preserves global cardiac function

Myocardial contractility Preserved1

Preserved2Ventricular repolarization time

Preserved2

1. Vilaine JP, Bidouard JP, Lesage BS, et al. J Cardiovasc Pharmacol. 2003;32:688-696.2. Camm A, Lau CP. Drugs R&D. 2003;4:83-89.

AV conduction time

Blood Pressure Preserved2

Pharmacological therapy for CHF patients

1. Diuretics

2. ACEI/ARB

3. Beta-blocker

4. Heart rate lowering

- Digoxin

- Ivabradine

Evidences of Ivabradine across Cardiovascular Continuum

Remodeling

Ventricular Dilation

Chronic Heart Failure

Myocardial Ischemia (angina)

AtherosclerosisLVH

Coronary Artery Disease

Coronary Thrombosis Arrhythmi

End-StageHeart Disease,Death

DyslipidemiaHypertensionDiabetesSmokingObesity

Myocardial Infarction

The Cardiovascular

Continuum

Dzau V et al. Circulation. 2006;114:2850-2870

INITIATIVEINITIATIVE

Stable CAD & Normal EF

CARVIVA HF

Ivabradine indicated for CAD patients

Symptomatic treatment of chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm:

•in patients with HR > 70 bpm- In addition to beta-blockers- As an alternative to beta-blockers

Ivabradine indicated for chronic heart failure

• Ivabradine is indicated in chronic heart failure NYHA II to IV class with systolic dysfunction, in patients in sinus rhythm and whose heart rate is ≥ 70 bpm

• In combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated

Typical Case

• 55 yo man, smoker , history of CAD 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 carvedilol 6.25mg bid, perindropril 5mg, ASA, plavix, statin, ISMN 50mg

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

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