A step further in the management
of stable coronary patients with ivabradine
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.
Design and Organization
MorBidity-mortality EvAlUation of The I f 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
10 917 participants with documented coronary artery disease
and left ventricular dysfunction
781 sites in 33 countries across 4 continents
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 (70 bpm)
fatal or nonfatal MI (%)
Hospitalization for
RRR 36%
4
Ivabradine
0
0 0.5 1 1.5 2
Years
RRR: relative risk reduction
Fox K et al. Lancet. 2008;372:807-816.
Ivabradine shifts the patients from
high risk to low risk
8
HR >70 bpm in placebo
(mean HR = 79 bpm)
-36%*
4 HR 70 bpm with Procoralan
(mean HR = 66 bpm after treatment)
0 *P=0.001
**P=0.0066
0 0.5 1 1.5 2
Years
Fox K et al. Lancet. 2008;372:807-816.
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%
4
Ivabradine
0
0 0.5 1 1.5 2
Years
RRR: relative risk reduction
Fox K et al. Lancet. 2008;372:807-816.
Ivabradine reduces all coronary events
in coronary patients with HR ≥70 bpm
Predefined end point Hazard Risk P value
ratio reduction
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, 0.77 23% 0.009
or revascularization
Coronary revascularization 0.70 30% 0.016
Fox K et al. Lancet. 2008;372:807-816.
Optimal reduction in heart rate in coronary
patients with HR ≥70 bpm
90
80 Placebo
70
60
Ivabradine
50
0 15 30 90 180 360 540 720
Follow-up (days)
Fox K, et al. Lancet. 2008;372:807-816.
New Results
In angina patients
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.
Design and methodology
New results in
angina patients
12 138 patients
with CAD and LVD
screened
10 917 randomized
1507 randomized
with angina
734 to Procoralan 773 to placebo
734 analyzed 773 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
New results in
angina patients
Patients with angina Total BEAUTIFUL population
Ivabradine Placebo Ivabradine Placebo
(n=734) (n=773)
Aspirin or 92% 92% 94% 94%
antithrombotic agent
Statin 67% 64% 74% 74%
ACE inhibitor and/or 88% 86% 90% 90%
ARB
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.
Ivabradine reduces primary end point
in angina patients
New results in
angina patients
Primary end point(PEP) : CV death + hospitalization for HF or MI
Cumulative incidence
20
Placebo
n=1507
P=0.05
-24%
for PEP* (%)
15
10 Ivabradine
5
0
0 0.5 1 1.5 2
Years
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.
Ivabradine reduces myocardial infarction in
patients with angina
New results in
angina patients
All patients with angina Patients with angina and
heart rate >70 bpm
15 15
Hospitalization for fatal and nonfatal MI Hospitalization for fatal and nonfatal MI
HR (95% CI), 0.58 (0.37–0.92); P=0.021 HR (95% CI), 0.27 (0.11–0.66); P=0.002
10
42% 10 73%
Event rate (%)
Event rate (%)
Placebo
Placebo
5 5
Ivabradine
0 0
Ivabradine
0 0.5 1 1.5 2 0 0.5 1 1.5 2
Years Years
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.
Summary of observed cardiovascular
risk reduction in angina patients
New results in
angina patients
Predefined end point Hazard Risk
(n=1507) ratio reduction
Primary composite end point 0.76 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%
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.
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
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