a step further in the management of stable coronary patients with ivabradine
TRANSCRIPT
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.
New results in angina patients
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
IvabradineIvabradine
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.
New results in angina patients
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
IvabradineIvabradine
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
IvabradineIvabradine
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%
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.
New results in angina patients
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)
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.
New results in angina patients
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