Transcript BEAUTIFUL - Ivabradine

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 (<40%)
 Clinically stable for 3 months with regards to angina or
heart failure symptoms or both
 Therapeutically stable for 1 month (appropriate or stable doses
of conventional medications)
K. Fox et al. Am Heart J. 2006;152:860-866.
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.
Patients and follow-up
12 138 screened
10 917 randomized
5479 to ivabradine
5438 to placebo
5479 analyzed
5438 analyzed
Median study duration: 19 months
Maximum: 35 months
Fox K et al. Lancet. 2008;372:807-816.
Baseline characteristics
Placebo
Ivabradine
All
8.2 (7.1)
8.1 (7.0)
8.2 (7.0)
89
88
88
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 coronary
revascularization (%)
52
51
52
Time since CAD diagnosis
(years)
Previous MI (%)
Time since last MI (years)
Values in parentheses are standard deviations
Fox K et al. Lancet. 2008;372:807-816.
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.
Results
Heart rate above 70 bpm increases
risk of myocardial infarction by 46%
Prospective data from the BEAUTIFUL placebo arm
% with hospitalization for
fatal and nonfatal MI
8
Hazard ratio = 1.46 (1.11 – 1.91)
P=0.0066
Heart rate ≥70 bpm
6
4
Heart rate <70 bpm
2
0
0
0.5
1
Years
Fox K et al. Lancet. 2008;372:817-821.
1.5
2
Heart rate above 70 bpm increases
risk of coronary revascularization by 38%
% with coronary revascularization
6
Hazard ratio = 1.38 (1.02 – 1.86)
P=0.037
Heart rate ≥70 bpm
4
2
Heart rate <70 bpm
0
0
0.5
1
Years
Fox K et al. Lancet. 2008;372:817-821
1.5
2
Effect of ivabradine on primary
endpoint (Overall population)
% with primary composite end point of CV death, hospitalization for acute MI, or for new-onset
or worsening heart failure
25
Hazard ratio = 1.00 (0.91 – 1.10)
P=0.94
Ivabradine
20
15
Placebo
10
5
0
0
Fox K et al. Lancet. 2008;372:807-816.
0.5
1
Years
1.5
2
Ivabradine reduces fatal and nonfatal
myocardial infarction (HR ≥70 bpm)
Hospitalization for
fatal or nonfatal MI (%)
8
Hazard ratio = 0.64 (0.49 – 0.84)
Placebo
P=0.001
(HR >70 bpm)
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%*
HR <70 bpm in placebo
4
(mean HR = 64 bpm)
HR > 70 bpm with Procoralan
(mean HR = 66 bpm after treatment)
0
*P=0.001
**P=0.0066
0
0.5
Fox K et al. Lancet. 2008;372:807-816.
1
Years
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%
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,
or revascularization
0.77
23%
0.009
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
Follow-up (days)
Fox K, et al. Lancet. 2008;372:807-816.
360
540
720
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
734 analyzed
773 to placebo
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
Ivabradine
Placebo
(n=734)
(n=773)
Total BEAUTIFUL population
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.
Ivabradine reduces primary end point
in angina patients
New results in
angina patients
Cumulative incidence
for PEP* (%)
Primary end point(PEP) : CV death + hospitalization for HF or MI
20
-24%
n=1507
P=0.05
15
Placebo
Ivabradine
10
5
0
0
0.5
1
Years
1.5
2
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
Patients with angina and
heart rate >70 bpm
All patients with angina
15
15
Hospitalization for fatal and nonfatal MI
HR (95% CI), 0.27 (0.11–0.66); P=0.002
Hospitalization for fatal and nonfatal MI
HR (95% CI), 0.58 (0.37–0.92); P=0.021
42%
Placebo
5
73%
10
Event rate (%)
Event rate (%)
10
Placebo
5
Ivabradine
0
Ivabradine
0
0
0.5
1
Years
1.5
2
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.
Summary of observed cardiovascular
risk reduction in angina patients
New results in
angina patients
Predefined end point
(n=1507)
Hazard
ratio
Risk
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