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A step further in the management of stable coronary patients with ivabradine. Rationale. RATIONALE . In CAD patients, high heart rate is associated with higher mortality 1 CAD patients with associated LVD are at higher risk of mortality 2

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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-Diaz A,et al. Eur Heart J.2005;26:867-874.2-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.

slide5

MorBidity-mortality EvAlUation of The If inhibitor Ivabradine in patients with coronary disease and left ventricULar dysfunction

  • Clinical objective

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

  • Pathophysiological objective

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

worldwide study
Worldwide study

10 917 participants with documented coronary artery diseaseand left ventricular dysfunction

781 sites in 33 countries across 4 continents

inclusion criteria
Inclusion 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.

slide8

Design of the study

Ivabradine 5 mg  7.5 mg 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

Placebo bid

Visits

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

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

slide9

Patients and follow-up

12 138 screened

10 917 randomized

5479 to ivabradine

5438 to placebo

5479 analyzed

5438 analyzed

Median study duration: 19 monthsMaximum: 35 months

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

baseline characteristics
Baseline characteristics

Placebo

Ivabradine

All

Time since CAD diagnosis(years)

8.2 (7.1)

8.1 (7.0)

8.2 (7.0)

Previous MI (%)

89

88

88

Time since last MI (years)

6.2 (6.0)

5.9 (5.7)

6.0 (5.9)

History of diabetes (%)

37

37

37

History of hypertension (%)

71

71

71

Previous coronaryrevascularization (%)

52

51

52

Values in parentheses are standard deviations

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

concomitant treatment
Concomitant treatment

Placebo

Ivabradine

All

Antithrombotic agents (%)

94

94

94

Statins (%)

74

74

74

-blockers (%)

87

87

87

Renin-angiotensin blockers (%)

90

90

90

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

slide13

0

0.5

1

1.5

2

Heart rate above 70 bpm increases

risk of myocardial infarction by 46%

Prospective data from the BEAUTIFUL placebo arm

8

Hazard ratio = 1.46 (1.11 – 1.91)

P=0.0066

Heart rate ≥70 bpm

6

% with hospitalization for

fatal and nonfatal MI

4

Heart rate <70 bpm

2

0

0

Years

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

slide14

Hazard ratio = 1.38 (1.02 – 1.86)

P=0.037

0

0.5

1

1.5

2

Heart rate above 70 bpm increases

risk of coronary revascularization by 38%

% with coronary revascularization

6

Heart rate ≥70 bpm

4

2

Heart rate <70 bpm

0

Years

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

effect of ivabradine on primary endpoint overall population

25

Hazard ratio = 1.00 (0.91 – 1.10)

P=0.94

Ivabradine

20

15

Placebo

10

5

0

0

0.5

1

1.5

2

Years

Effect of ivabradine on primaryendpoint (Overall population)

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

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

ivabradine reduces fatal and nonfatal myocardial infarction hr 70 bpm

Hazard ratio = 0.64 (0.49 – 0.84)

P=0.001

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

8

Placebo

(HR >70 bpm)

RRR 36%

Hospitalization for

fatal or nonfatal MI (%)

4

Ivabradine

0

0

0.5

1

1.5

2

Years

RRR: relative risk reduction

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

slide17

-36%*

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

Ivabradine shifts the patients from high risk to low risk

8

HR >70 bpm in placebo

(mean HR = 79 bpm)

4

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

Hospitalization for

fatal or nonfatal MI (%)

0

*P=0.001

**P=0.0066

0

0.5

1

1.5

2

Years

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

slide18

0

0.5

1

1.5

2

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

8

Hazard ratio = 0.70 (0.52 – 0.93)

P=0.016

Placebo

(HR >70 bpm)

RRR 30%

Coronary revascularization (%)

4

Ivabradine

0

Years

RRR: relative risk reduction

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

slide19

Fatal MI

0.69

31%

0.114

Fatal and nonfatal MI

0.64

36%

0.001

Fatal and nonfatal MI or unstable angina

0.78

22%

0.023

Fatal and nonfatal MI, unstable angina,or revascularization

0.77

23%

0.009

Coronary revascularization

0.70

30%

0.016

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

Predefined end point

Hazardratio

Riskreduction

P value

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

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

90

80

Placebo

70

Heart rate (bpm)

60

Ivabradine

50

540

0

360

720

180

15

30

90

Follow-up (days)

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

new results

New Results

In angina patients

slide22

New 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.

slide23

Design and methodology

New results in angina patients

12 138 patients with CAD and LVD screened

10 917 randomized

1507 randomized

with angina

773 to placebo

734 to Procoralan

773 analyzed

734 analyzed

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.

baseline treatment
Baseline treatment

New results in angina patients

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.

slide25

20

Placebo

-24%

n=1507

P=0.05

15

Cumulative incidence

for PEP* (%)

Ivabradine

10

5

0

0

0.5

1

1.5

2

Years

Ivabradine reduces primary end point in angina patients

New results in angina patients

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

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.

slide26

15

15

Hospitalization for fatal and nonfatal MI

HR (95% CI), 0.58 (0.37–0.92); P=0.021

Hospitalization for fatal and nonfatal MI

HR (95% CI), 0.27 (0.11–0.66); P=0.002

42%

73%

10

10

Placebo

Event rate (%)

Placebo

Event rate (%)

5

5

Ivabradine

Ivabradine

0

0

0

0.5

1

1.5

2

0

0.5

1

1.5

2

Years

Years

Ivabradine reduces myocardial infarction in patients with angina

New results in angina patients

Patients with angina and

heart rate >70 bpm

All patients with angina

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.

slide27

Hazardratio

Riskreduction

Predefined end point

0.76

Primary composite end point

24%

All-cause mortality

0.87

13%

CV death

0.88

12%

Hospitalization for HF

0.84

16%

Hospitalization for MI

0.58

42%

Coronary revascularization

0.70

30%

Summary of observed cardiovascular risk reduction in angina patients

New results in angina patients

(n=1507)

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.

slide28

In brief

  • 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.
organization
Organization

Executive Committee:

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

Steering Committee:

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

End Point Validation Committee:

K. Thygesen (Chairman); M. Frenneaux; G. Jondeau

Data Monitoring Committee:

A.J. Camm (Chairman); G. Murray; H. Dargie, L. Tavazzi