A step further in the management of stable coronary patients with ivabradine.

A step further in the management of stable coronary patients with ivabradine

RationaleRationale

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.

Design and Design and OrganizationOrganization

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

with coronary disease and left ventricwith coronary disease and left ventricULULar dysfunctionar dysfunction

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

with coronary disease and left ventricwith 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

IvabradineIvabradine

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

Ivabradine Ivabradine

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).

Procoralan has established anti-ischemic and antianginal efficacy.

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

Objective

To explore the effects of Procoralan 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 Procoralan 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

OrganizatioOrganizationn

Executive CommitteeExecutive Committee::K. Fox K. Fox (Chairman),(Chairman), R. Ferrari, M. Tendera, P.G. Steg, I. Ford R. Ferrari, M. Tendera, P.G. Steg, I. Ford

Steering CommitteeSteering Committee::R. Ferrari R. Ferrari (Chairman),(Chairman), Y. Belenkov Y. Belenkov (Russia),(Russia), J. Borbola J. Borbola (Hungary),(Hungary), R. Capalneanu R. Capalneanu (Romania),(Romania), B. Eber B. Eber (Austria),(Austria), J. Eha J. Eha (Estonia),(Estonia), N. Danchin N. Danchin (France),(France), M. Dellborg M. Dellborg (Sweden),(Sweden), K. Dickstein K. Dickstein (Norway),(Norway), B. Finkov and Y. Yotov B. Finkov and Y. Yotov (Bulgaria),(Bulgaria), B. Freedman B. Freedman (Australia),(Australia), H. Grancelli H. Grancelli (Argentina),(Argentina), A. Hall A. Hall (United Kingdom),(United Kingdom), P. Hildebrandt P. Hildebrandt (Denmark),(Denmark), J. Hradec J. Hradec (Czech Republic),(Czech Republic), D. Hu and C. D. Hu and C. Lau Lau (China/Hong Kong),(China/Hong Kong), J. Jirgensons J. Jirgensons (Latvia),(Latvia), A. Laucevicius A. Laucevicius (Lithuania),(Lithuania), T.U. Lqscher T.U. Lqscher (Switzerland),(Switzerland), C. Macaya C. Macaya (Spain),(Spain), A. Maggioni A. Maggioni (Italy),(Italy), T. Meinertz T. Meinertz (Germany),(Germany), D. Mulcahy D. Mulcahy (Ireland),(Ireland), J. Murin J. Murin (Slovakia),(Slovakia), A. Oto A. Oto (Turkey),(Turkey), A. Parkhomenko A. Parkhomenko (Ukraine),(Ukraine), K. Peuhkurinen K. Peuhkurinen (Finland),(Finland), P. Rakovec P. Rakovec (Slovenia),(Slovenia), W. Ruzyllo W. Ruzyllo (Poland),(Poland), R. Seabra-Gomes R. Seabra-Gomes (Portugal),(Portugal), J.C. Tardif J.C. Tardif (Canada),(Canada), W. Van Gilst W. Van Gilst (The Netherlands),(The Netherlands), J.L. Vanoverschelde J.L. Vanoverschelde (Belgium),(Belgium), P. Vardas P. Vardas (Greece)(Greece)

End Point Validation CommitteeEnd Point Validation Committee::K. Thygesen K. Thygesen (Chairman)(Chairman); M. Frenneaux; G. Jondeau; M. Frenneaux; G. Jondeau

Data Monitoring CommitteeData Monitoring Committee::A.J. Camm A.J. Camm (Chairman)(Chairman); G. Murray; H. Dargie, L. Tavazzi; G. Murray; H. Dargie, L. Tavazzi

A step further in the management of stable coronary patients with ivabradine.

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Transcript of A step further in the management of stable coronary patients with ivabradine.