1 Ivabradine Dr.Rajesh Rajan M.D.,D.Card,FACC,FAHA,FESC PRESIDENT – IACC .

1

IvabradineIvabradine

Dr.Rajesh RajanDr.Rajesh Rajan M.D.,D.Card,FACC,FAHA,FESCM.D.,D.Card,FACC,FAHA,FESC

PRESIDENT – IACC www.accindia.orgPRESIDENT – IACC www.accindia.org

2

Elevated Resting Heart RateElevated 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)

3

Beta-AdrenoceptorsBeta-Adrenoceptors

Endogenous catecholamines

activate B-receptors

(Adenylate Cyclase)

Increased cAMP

Increased Ca++ influx

Inotropic Chronotropic

4

Beta Blockers (BB)Beta Blockers (BB)

B1negative chronotropy and inotropy

AV conduction delay

Reduced atrial and ventricular arrythmias

B2Bronchoconstriction

Peripheral unopposed alpha constriction

Decrease glycogenolysis

• (contribute to hypoglycemic events)

Other antagonize release of renin

reduces intraocular pressures

5

Impact of BBImpact of BB

Acute MI

– Norwegian Multicenter Study Group Timolol *

– CAPRICORN †

– ISIS-1 ‡

CHF

– COPERNICUS £

– MERIT-HF €

6

Intolerence of BBIntolerence 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): 579-586

IIff Current Current

The funny current is highly expressed in spontaneously active cardiac regions, such as the sinoatrial node (SAN, the natural pacemaker region), the atrio-ventricular node (AVN) and the Purkinje fibres of conduction tissue.

Particularly unusual, the funny current is a mixed sodium-potassium current, inward and slowly activating on hyperpolarization at voltages in the diastolic range (normally from -60/-70 mV to -40 mV).

When at the end of a sinoatrial action potential the membrane repolarizes below the If threshold (about -40/-50 mV), the funny current is activated and supplies inward current, which is responsible for starting the diastolic depolarization phase (DD);

By this mechanism, the funny current controls the rate of spontaneous activity of sinoatrial myocytes, hence the cardiac rate.

http://en.wikipedia.org/wiki/Sinoatrial_node

http://en.wikipedia.org/wiki/Sinoatrial_node

http://en.wikipedia.org/wiki/Atrioventricular_node

http://en.wikipedia.org/wiki/Atrioventricular_node

http://en.wikipedia.org/wiki/Diastolic_depolarization

IIff Current Current

Another unusual feature of If is its dual activation by voltage and by cyclic nucleotides. Cyclic adenosine monophosphate (cAMP) molecules bind directly to f-channels and increase their open probability. cAMP dependence is a particularly relevant physiological property,

Since it underlies the If –dependent autonomic regulation of heart rate. Sympathetic stimulation raises the level of cAMP molecules which bind to f-channels and shift the If activation range to more positive voltages;

This mechanism leads to an increase of the current at diastolic voltages and therefore to an increase of the steepness of DD and heart rate acceleration.

Parasympathetic stimulation (which acts to increase probability of potassium channels opening but decreases the probability of calcium channel opening) decreases the heart rate by the opposite action, that is by shifting the If activation curve towards more negative voltages.

9


Specifically binds the Funny channel

– Reduces the slope for diastolic depolarization

• Prolongs diastolic duration

Does not alter…

• Ventricular repolarization

• Myocardial contractility

• Blood pressure

10

Ivabradine TrialsIvabradine Trials

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

– 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;26:2529-36)

– Exercise tolerance, time to angina or ischemia

Non-inferior to Amlodipine (Drugs 2007;67(3):393-405)

MorMorBBidity-mortality idity-mortality EEvvAAllUUation of ation of TThe he II ff

inhibitor Ivabradine in patients with coronary inhibitor Ivabradine in patients with coronary

disease and left ventricdisease and left ventricULULar dysfunctionar dysfunction

BEAUTIFUL TrialBEAUTIFUL Trial

RATIONALE RATIONALE

In CAD patients, high heart rate is associated with higher mortality1

CAD patients with associated LVD are at higher risk of mortality2

Heart rate reduction could reduce mortality in CAD patients3

Ivabradine is a pure heart rate reducing agent with proven antianginal and anti-ischemic efficacy 4,5,6

1-1- Diaz A,et al. . Eur Heart J.. 2005;26:867-874. 2-2- Emond M. Circulation. 1994;90:2645–2657. 3- Cucherat Ml. Eur Heart J. 2007;28:3012-3019. 4- Borer JS et al. Circulation. 2003;107:817-823. 5- Tardif JC,et al. Eur Heart J. 2009;30:540-548 6- Tardif JC et al. Eur Heart J. 2005;26:2529-2536.

MorMorBBidity-mortality idity-mortality EEvvAAllUUation of ation of TThe he II ff inhibitor Ivabradine in inhibitor Ivabradine in

patients with coronary disease and left ventricpatients with coronary disease and left ventricULULar dysfunctionar dysfunction

MorMorBBidity-mortality idity-mortality EEvvAAllUUation of ation of TThe he II ff inhibitor Ivabradine in inhibitor Ivabradine in

patients with coronary disease and left ventricpatients with coronary disease and left ventricULULar dysfunctionar dysfunction

Clinical objective Clinical objective

To examine the effects of elevated HR (>70 bpm) on cardiovascular events in these coronary patients

Pathophysiological objective Pathophysiological objective

To examine the effects of ivabradine on cardiovascular events in coronary patients with left ventricular dysfunctionTo examine the effects of ivabradine on cardiovascular events in coronary patients with left ventricular dysfunction

Worldwide studyWorldwide study

10 917 participants with documented coronary artery diseaseand left ventricular dysfunction

781 sites in 33 countries across 4 continents

Inclusion criteriaInclusion criteria

Male or female

Nondiabetic 55 years, diabetic 18 years

Documented coronary artery disease

Sinus rhythm and resting heart rate 60 bpm

Documented left ventricular systolic dysfunction (<40%)

Clinically stable for 3 months with regards to angina orheart failure symptoms or both

Therapeutically stable for 1 month (appropriate or stable dosesof conventional medications)

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

Design of the studyDesign of the study

Visits

Follow-up for 12 to 35 months–median 19 months

Ivabradine 5 mg 7.5 mg bid

Placebo bid

Multicenter (781 centers / 33 countries) randomized trial

10 917 patients with stable CAD and left ventricular dysfunction (EF <40%)

Already receiving appropriate conventional cardiovascular medical therapy

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

Patients and follow-upPatients and follow-up

Median study duration: 19 monthsMedian study duration: 19 monthsMaximum: 35 monthsMaximum: 35 months

Median study duration: 19 monthsMedian study duration: 19 monthsMaximum: 35 monthsMaximum: 35 months

10 917 randomized

5479 to ivabradine 5438 to placebo

5438 analyzed5479 analyzed

12 138 screened

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

Baseline characteristicsBaseline characteristics

Values in parentheses are standard deviations

PlaceboPlacebo IvabradineIvabradine

History of diabetes (%)History of diabetes (%) 3737 3737 3737

Time since last MI (years)Time since last MI (years) 6.2 (6.0)6.2 (6.0) 5.9 (5.7)5.9 (5.7) 6.0 (5.9)6.0 (5.9)

Time since CAD diagnosisTime since CAD diagnosis(years)(years)

8.2 (7.1)8.2 (7.1) 8.1 (7.0)8.1 (7.0) 8.2 (7.0)8.2 (7.0)

History of hypertension (%) History of hypertension (%) 7171 7171 7171

Previous coronaryPrevious coronaryrevascularization (%)revascularization (%) 5252 5151 5252

AllAll

Previous MI (%)Previous MI (%) 8989 8888 8888

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

Concomitant treatmentConcomitant treatment

-blockers (%)-blockers (%)

Statins (%)Statins (%)

Antithrombotic agents (%)Antithrombotic agents (%)

Renin-angiotensin blockers (%) Renin-angiotensin blockers (%)

8787

7474

9494

9090

PlaceboPlacebo

8787

7474

9494

9090


8787

7474

9494

9090

AllAll

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

ResultsResults

Years

P=0.0066

Hazard ratio = 1.46 (1.11 – 1.91)

0 0.5 1 1.5 2

0

Heart rate <70 bpm

Heart rate ≥70 bpm

8

% w

ith

ho

sp

ital

izat

ion

fo

r f

ata

l an

d n

on

fata

l M

I

0

4

6

2

Heart rate above 70 bpm increasesHeart rate above 70 bpm increases risk of myocardial infarction by 46%risk of myocardial infarction by 46%

Prospective data from the BEAUTIFUL placebo arm

Fox K et al. Lancet. 2008;372:817-821.

% with coronary revascularization

Years

P=0.037

Hazard ratio = 1.38 (1.02 – 1.86)

0 0.5 1 1.5 2

0

4

6

2Heart rate <70 bpm

Heart rate ≥70 bpm

Heart rate above 70 bpm increasesHeart rate above 70 bpm increases risk of coronary revascularization by 38%risk of coronary revascularization by 38%

Fox K et al. Lancet. 2008;372:817-821

Effect of ivabradine on Effect of ivabradine on primaryprimary

endpoint (Overall population)endpoint (Overall population)

% with primary composite end point of CV death, hospitalization for acute MI, or for new-onset

or worsening heart failure

Ivabradine

Placebo

P=0.94

Hazard ratio = 1.00 (0.91 – 1.10)

0

5

10

15

20

25

Years0 0.5 1 1.5 2

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

Ivabradine reduces fatal and nonfatal Ivabradine reduces fatal and nonfatal myocardial infarction (HR ≥70 bpm)myocardial infarction (HR ≥70 bpm)

Ho

spit

aliz

atio

n f

or

fata

l o

r n

on

fata

l M

I (%

)

Placebo(HR >70 bpm)

Ivabradine Ivabradine

P=0.001

Hazard ratio = 0.64 (0.49 – 0.84)

Years

0 0.5 1 1.5 2

0

4

8

RRR 36%

RRR: relative risk reduction

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

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

HR >70 bpm in placebo (mean HR = 79 bpm)

*P=0.001**P=0.0066

Years

Ho

spit

aliz

atio

n f

or

fata

l o

r n

on

fata

l M

I (%

)

HR > 70 bpm with Procoralan (mean HR = 66 bpm after treatment)

HR > 70 bpm with Procoralan (mean HR = 66 bpm after treatment)

0 0.5 1 1.5 2

0

4

8

HR <70 bpm in placebo(mean HR = 64 bpm)

Ivabradine shifts the patients from Ivabradine shifts the patients from high risk to low riskhigh risk to low risk

Ivabradine shifts the patients from Ivabradine shifts the patients from high risk to low riskhigh risk to low risk

-36%*-36%*

Years

0 0.5 1 1.5 2

0

4


8

Co

ron

ary

reva

scu

l ari

zati

on

(%

)

P=0.016

Hazard ratio = 0.70 (0.52 – 0.93)

RRR 30%

Placebo(HR >70 bpm)

Ivabradine reduces the need for Ivabradine reduces the need for revascularization (HR ≥70 bpm)revascularization (HR ≥70 bpm)

RRR: relative risk reduction

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

0.1140.11431%31%0.690.69Fatal MIFatal MI

0.0230.02322%22%0.780.78Fatal and nonfatal MI or unstable anginaFatal and nonfatal MI or unstable angina

0.0160.01630%30%0.700.70Coronary revascularizationCoronary revascularization

0.0090.00923%23%0.770.77Fatal and nonfatal MI, unstable angina,Fatal and nonfatal MI, unstable angina,or revascularizationor revascularization

0.0010.00136%36%0.640.64Fatal and nonfatal MIFatal and nonfatal MI

PP value valueRiskRiskreductionreduction

HazardHazardratioratio

Predefined end pointPredefined end point

Ivabradine reduces all coronary events Ivabradine reduces all coronary events in coronary patients with HR ≥70 bpmin coronary patients with HR ≥70 bpm

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

Optimal reduction in heart rate in coronary Optimal reduction in heart rate in coronary patients with HR ≥70 bpmpatients with HR ≥70 bpm

Hea

rt r

ate

(b

pm

)

Follow-up (days)

50

60

80

0 15 30 90 180 360 540 720

70

Placebo

Ivabradine

90

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

New ResultsNew Results

In angina patients

Rationale

Angina is the most common clinical manifestation of coronary artery disease (CAD).

Ivabradine has established anti-ischemic and antianginal efficacy.

In the large BEAUTIFUL trial, Ivabradine demonstrates that it reduces coronary events in CAD patients.

Objective

To explore the effects of Ivabradine on cardiovascular outcomes

in BEAUTIFUL patients with limiting angina at baseline.

New results in angina patientsNew results in angina patients

Design and methodologyDesign and methodology

1507 randomizedwith angina

734 to Ivabradine 773 to placebo

773 analyzed734 analyzed

12 138 patients with CAD and LVD

screened

10 917 randomized

Fox K, Ford I, et al; BEAUTIFUL Investigators. Effect of ivabradine on cardiovascular outcomes in patients with stable coronary artery diseaseand left-ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Data on file.

New results in angina patients

Baseline treatmentBaseline treatment

Patients with angina Total BEAUTIFUL population

Ivabradine

(n=734)Placebo

(n=773)Ivabradine Placebo

Aspirin or antithrombotic agent

92% 92% 94% 94%

Statin 67% 64% 74% 74%

ACE inhibitor and/or ARB

88% 86% 90% 90%

β-Blocker 89% 90% 87% 87%

Fox K, Ford I, et al; BEAUTIFUL Investigators. Effect of ivabradine on cardiovascular outcomes in patients with stable coronary artery diseaseand left-ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur heart Jour On line.


IvabradineIvabradine reduces primary end point reduces primary end point in angina patientsin angina patients

n=1507

P=0.05

Years

0

5

10

15

20

0 0.5 1 1.5 2

Cu

mu

lati

ve i

nci

de

nce

fo

r P

EP

*

(%) -24%-24%

Placebo


Primary end point(PEP) : CV death + hospitalization for HF or MI



Ivabradine reduces myocardial infarction in Ivabradine reduces myocardial infarction in patients with angina patients with angina

All patients with angina Patients with angina andheart rate >70 bpm

Placebo


Hospitalization for fatal and nonfatal MIHR (95% CI), 0.58 (0.37–0.92); P=0.021

Years

0

5

10

15

0 0.5 1 1.5 2

Eve

nt

rate

(%

)

42%42%

Placebo


Hospitalization for fatal and nonfatal MIHR (95% CI), 0.27 (0.11–0.66); P=0.002

Years

0

5

10

15

0 0.5 1 1.5 2

Eve

nt r

ate

(%)

73%73%



Summary of observed cardiovascular Summary of observed cardiovascular risk reduction in angina patientsrisk reduction in angina patients

24%0.76Primary composite end point

12%0.88CV death

42%0.58

16%0.84Hospitalization for HF

13%0.87All-cause mortality

Riskreduction

Hazardratio

Predefined end point

30%0.70Coronary revascularization

Hospitalization for MI

(n=1507)



Ivabradine, the first selective and specific If inhibitor, has already

demonstrated antianginal and anti-ischemic efficacy and improvement of cardiac performance

BEAUTIFUL, the first morbidity-mortality trial with ivabradine, includes 10 917 patients with documented stable coronary artery disease and left ventricular dysfunction receiving optimal guidelines-based therapy.

– In patients with coronary artery disease and left ventricular dysfunction, those with a heart rate >70 bpm have a higher risk of cardiovascular mortality, hospitalization for myocardial infarction, and heart failure.

– In patients with heart rate >70 bpm, ivabradine reduces the composite of fatal and nonfatal myocardial infarction and reduces the need for revascularisation.

– In angina patients, ivabradine reduces the primary end point of cardiovascular death, hospitalization for heart failure, or for myocardial infarction.

In briefIn brief

SSystolic ystolic HHeart failure treatment witheart failure treatment with

the the IfIf inhibitor ivabradine inhibitor ivabradine TTrialrial

SHIFT TrialSHIFT Trial

SSystolic ystolic HHeart failure treatment witheart failure treatment with

the the IfIf inhibitor ivabradine inhibitor ivabradine TTrialrial

SHIFT TrialSHIFT Trial

http://www.lancet.com published online August 29, 2010 DOI:10.1016/S0140-6736(10)61198-1

Background

Elevated heart rate is associated with poor outcome in a number of cardiovascular conditions including heart failure

Heart rate remains elevated in many heart failure patients despite treatment by beta-blockers

Ivabradine is a novel heart rate-lowering agent acting by inhibiting the If current in the sino-atrial node

We hypothesized that the addition of ivabradine to recommended therapy would be beneficial in heart failure patients with elevated heart rate

Primary objectivePrimary objective

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

improves cardiovascular outcomes improves cardiovascular outcomes

in patients within patients with

1. Moderate to severe chronic heart failure1. Moderate to severe chronic heart failure

2. Left ventricular ejection fraction 2. Left ventricular ejection fraction 35%35%

3. Heart rate 3. Heart rate 70 bpm and70 bpm and

4. Recommended therapy4. Recommended therapy

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

improves cardiovascular outcomes improves cardiovascular outcomes

in patients within patients with

1. Moderate to severe chronic heart failure1. Moderate to severe chronic heart failure

2. Left ventricular ejection fraction 2. Left ventricular ejection fraction 35%35%

3. Heart rate 3. Heart rate 70 bpm and70 bpm and

4. Recommended therapy4. Recommended therapy

Europe

Germany Portugal

Belgium Greece Spain

Denmark Ireland Sweden

Finland Italy Turkey

France The Netherlands UK

Bulgaria

Czech Republic

Estonia

Hungary

South America

Argentina

Brazil

Chili

North America

Canada

Asia

China

Hong Kong

India

South Korea

Malaysia

AustraliaAustralia

Latvia

Lithuania

Norway

Poland

Romania

Russia

Slovakia

Slovenia

Ukraine

Multinational studyMultinational studyMultinational studyMultinational study

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

18 years

Class II to IV NYHA heart failure

Ischaemic/non-ischaemic aetiology

LV systolic dysfunction (EF 35%)

Heart rate 70 bpm

Sinus rhythm

Documented hospital admission for worsening heart failure 12 months

Inclusion criteriaInclusion criteria

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

Study designStudy design

HR and tolerabilityIvabradine 5 mg bid

Matching placebo, bid

Every 4 monthsD0 D14 D28 M4

Ivabradine 7.5/5/2.5 mg bid according to


3.5 years

Screening 7 to 30 days

Study endpointsStudy endpoints

Cardiovascular death Hospitalization for worsening heart failure

Primary composite endpointPrimary composite endpoint

Other endpointsOther 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 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

Patients and follow-up

Median study duration: 22.9 months; maximum: 41.7 monthsMedian study duration: 22.9 months; maximum: 41.7 monthsMedian study duration: 22.9 months; maximum: 41.7 monthsMedian study duration: 22.9 months; maximum: 41.7 months

6558 randomized

3268 to ivabradine 3290 to placebo

3264 analysed

1 lost to follow-up

3241 analysed

2 lost to follow-up

7411 screened

Excluded: 27Excluded: 27 Excluded: 26Excluded: 26

Baseline characteristics


32413241

PlaceboPlacebo

32643264

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

Baseline characteristics


32413241

PlaceboPlacebo

32643264

Mean heart rate, bpmMean heart rate, bpm 8080 8080

Mean LVEF, %Mean LVEF, % 2929 2929

Mean SBP, mm HgMean SBP, mm Hg 122122 121121

Mean DBP, mm HgMean DBP, mm Hg 7676 7676

eGFR, mL/min/1.73 meGFR, mL/min/1.73 m22 7575 7575

Chronic HF background treatment

89 9184

61

22

3

90 91

83

59

22

40

10

20

30

40

50

60

70

80

90

100

Beta-blockers ACEIs and/orARBs

Diuretics Aldosterone antagonists

Digitalis ICD/CRT

Ivabradine

Placebo

Patients (%)Patients (%)Patients (%)Patients (%)

Background beta-blocker treatment

0

10

20

30

40

50

60

70

80

90

100

BB at

randomization

At least 50%

target daily dose

Target daily dose

89

56

26

Ivabradine

Placebo89

56

26

Patients (%)Patients (%)Patients (%)Patients (%)

Mean heart rate reduction Mean heart rate reduction

Mean ivabradine dose: 6.4 mg bid at 1 monthMean ivabradine dose: 6.4 mg bid at 1 month

6.5 mg bid at 1 year6.5 mg bid at 1 year

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

Months

90

80

70

60

50

67

7575

80

64

Ivabradine

Placebo

Heart rate (bpm)Heart rate (bpm)Heart rate (bpm)Heart rate (bpm)

Ivabradine n=793 (14.5%PY) Placebo n=937 (17.7%PY)

HR = 0.82 [[95% CI 0.75-0.900.75-0.90] p<0.0001

0 6 12 18 24 30

Months

40

30

20

10

0

Ivabradine

Placebo

Primary composite endpointPrimary composite endpoint

- 18%

Cumulative frequency (%)Cumulative frequency (%)Cumulative frequency (%)Cumulative frequency (%)


HR = 0.74 [[95% CI 0.66-0.830.66-0.83] p<0.0001

0 6 12 18 24 30

Months

30

20

10

0

Ivabradine

Placebo

Hospitalization for heart failureHospitalization for heart failure

- 26%



HR = 0.91 p=0.128

0 6 12 18 24 30

Months

30

20

10

0

Ivabradine

Placebo

Cardiovascular deathCardiovascular death


Effect of ivabradine on outcomes Effect of ivabradine on outcomes

EndpointsEndpoints Hazard ratioHazard ratio 95% CI95% CI pp value value

Primary composite endpoint 0.820.82 [0.75;0.90][0.75;0.90] pp<0.0001<0.0001

All-cause death 0.900.90 [0.80;1.02][0.80;1.02] pp=0.092=0.092

Death from HF 0.740.74 [0.58;0.94][0.58;0.94] pp=0.014=0.014

Hospitalisation for any cause 0.890.89 [0.82;0.96][0.82;0.96] pp=0.003=0.003

Hospitalisation for CV reason 0.850.85 [0.78;0.92][0.78;0.92] pp=0.0002=0.0002

CV death/hospitalisation for HF or non-fatal MI

0.820.82 [0.74;0.89][0.74;0.89] pp<0.0001<0.0001

Age <65 years ≥65 years

Sex Male

Female

Beta-blockers No Yes

Aetiology of heart failure Non-ischaemic

IschaemicNYHA class NYHA class II

NYHA class III or IVDiabetes No Yes

Hypertension No Yes

Baseline heart rate <77 bpm

≥77 bpm

Test for interaction

p=0.029

1.51.00.5Hazard ratio

Favours ivabradine Favours placebo

Effect of ivabradine in Effect of ivabradine in prespecified subgroupsprespecified subgroups

1.51.00.5Hazard ratio

Favours ivabradine Favours placebo

Ivabradine Hazard ratio

Primary compositeendpoint 330

(11.9 PY)

0.90362

(13.3 PY)

Cardiovascular death 176

(5.9 PY)

1.00175

(5.9 PY)

Hospitalisation forworsening HF 213

(7.7 PY)

0.81260

(9.6 PY)

Placebo

Patients with at least 50% BB Patients with at least 50% BB target dose target dose (n=3181)(n=3181)

pp value value

nsns

nsns

pp=0.021=0.021

NYHA class changesNYHA class changes

28

68

5

24

70

6

0

10

20

30

40

50

60

70

Improvement Stability Worsening

Ivabradine

Placebo

pp=0.0003=0.0003pp=0.0003=0.0003PatientsPatients (%) (%)PatientsPatients (%) (%)

Incidence of selected adverse Incidence of selected adverse events events (N = 6492)(N = 6492)

Patients with an eventPatients with an event


N=3232, % N=3232, % (n)

Placebo Placebo

N=3260, N=3260, %% (n)

pp value value

All serious adverse events 45% 45% (1450) 48% 48% (1553) 0.0250.025

All adverse events 75% 75% (2439) 74% 74% (2423) 0.3030.303

Heart failure 25% 25% (804) 29% 29% (937) 0.00050.0005

Symptomatic bradycardia 5% 5% (150) 1% 1% (32) <0.0001<0.0001

Asymptomatic bradycardia 6% 6% (184) 1% 1% (48) <0.0001<0.0001

Atrial fibrillation 9% 9% (306) 8% 8% (251) 0.0120.012

Phosphenes 3% 3% (89) 1% 1% (17) <0.0001<0.0001

Blurred vision 1% 1% (17) <1% <1% (7) 0.0420.042

ConclusionConclusion

Heart failure with systolic dysfunctionwith systolic dysfunction and elevated heart rate

is associated with poor outcomes (primary composite endpoint

in the placebo group is 18%/year)

Ivabradine reduced CV mortality or heart failure hospitalization

by 18% (p<0.0001). The absolute risk reduction was 4.2%

This beneficial effect was mainly driven by a favourable effect

on heart failure death/hospital admission (RRR 26%)

Overall, treatment with ivabradine was safe and well tolerated

ESC - 2012

Should be considered to reduce the risk of HF hospitalization in

patients in sinus rhythm with an EF ≤35%, a heart rate remaining ≥70

b.p.m., and persisting symptoms (NYHA class II–IV) despite treatment

with an evidence-based dose of beta-blocker (or maximum tolerated dose

below that), ACE inhibitor (or ARB), and an MRA (or ARB).

- IIa B May be considered to reduce the risk of HF hospitalization in patients in

sinus rhythm with an EF ≤35% and a heart rate ≥70 b.p.m. who are unable to

tolerate a beta-blocker. Patients should also receive an ACE inhibitor (or ARB)

and an MRA (or ARB). ]

- IIb C

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1 Ivabradine Dr.Rajesh Rajan M.D.,D.Card,FACC,FAHA,FESC PRESIDENT – IACC .

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Transcript of 1 Ivabradine Dr.Rajesh Rajan M.D.,D.Card,FACC,FAHA,FESC PRESIDENT – IACC .