Transcript BEAUTIFUL

Ivabradine
Dr.Rajesh Rajan
M.D.,D.Card,FACC,FAHA,FESC
PRESIDENT – IACC www.accindia.org
1
Elevated Resting Heart Rate
 Accelerates production of atherosclerosis (Int J Cardiol 2008;126:302-12)
 Associated with coronary plaque disruption (Circulation 2001;126:1477-82)
 Framingham Study
– progressive increase in all cause and cardiovascular mortality in relation
to antecedent HR (Am Heart J 1987; 113:1489-94)
 Continuous increase in death rates in survivors of Acute MI
starting at HR > 70 (J Am Coll Cardiol 2007;50:823-30)
2
Beta-Adrenoceptors


Endogenous
catecholamines
activate B-receptors

(Adenylate Cyclase)
 Increased cAMP
 Increased Ca++ influx
Inotropic
Chronotropic
3
Beta Blockers (BB)
 B1negative chronotropy and inotropy
 AV conduction delay
 Reduced atrial and ventricular arrythmias
 B2Bronchoconstriction
 Peripheral unopposed alpha constriction
 Decrease glycogenolysis
• (contribute to hypoglycemic events)

 Other antagonize release of renin

reduces intraocular pressures
4
Impact of BB
 Acute MI
– Norwegian Multicenter Study Group Timolol *
– CAPRICORN †
– ISIS-1 ‡
 CHF
– COPERNICUS £
– MERIT-HF €
5
Intolerence of BB
 Side effects
– Bronchoconstriction, AV delay, hypoglycemia
– Weight gain, depression, fatigue
 BB may not be tolerated in high enough doses to attain
heart rates below 70bpm
 Acute setting (Acute MI, or CHF), the negative inotropic
effect could be deleterious
– This has been shown in dogs (Eur Heart J (2004) 25 (7): 579-586
6
If Current
 The funny current is highly expressed in spontaneously active cardiac regions,
such as the sinoatrial node (SAN, the natural pacemaker region), the atrioventricular node (AVN) and the Purkinje fibres of conduction tissue.
 Particularly unusual, the funny current is a mixed sodium-potassium current,
inward and slowly activating on hyperpolarization at voltages in the diastolic
range (normally from -60/-70 mV to -40 mV).
 When at the end of a sinoatrial action potential the membrane repolarizes below
the If threshold (about -40/-50 mV), the funny current is activated and supplies
inward current, which is responsible for starting the diastolic
depolarization phase (DD);

By this mechanism, the funny current controls the rate of spontaneous activity
of sinoatrial myocytes, hence the cardiac rate.
If Current
 Another unusual feature of If is its dual activation by voltage and by cyclic
nucleotides. Cyclic adenosine monophosphate (cAMP) molecules bind
directly to f-channels and increase their open probability. cAMP dependence
is a particularly relevant physiological property,
 Since it underlies the If –dependent autonomic regulation of heart rate.
Sympathetic stimulation raises the level of cAMP molecules which bind to fchannels and shift the If activation range to more positive voltages;
 This mechanism leads to an increase of the current at diastolic voltages and
therefore to an increase of the steepness of DD and heart rate acceleration.
 Parasympathetic stimulation (which acts to increase probability of potassium
channels opening but decreases the probability of calcium channel opening)
decreases the heart rate by the opposite action, that is by shifting the
If activation curve towards more negative voltages.
Ivabradine
 Specifically binds the Funny channel
– Reduces the slope for diastolic depolarization
• Prolongs diastolic duration
 Does not alter…
• Ventricular repolarization
• Myocardial contractility
• Blood pressure
9
Ivabradine Trials
 Reduces atherosclerosis (Circ 2008;117:2377-87)
– Decreases vascular oxidative stress
– Improves endothelial function
 Increases exertional tolerance and time to ischemia in
patients with > 3 months angina (Circ 2003;107:817-23)
 Non-inferior to Atenolol (Eur Heart J 2005;26:2529-36)
– Exercise tolerance, time to angina or ischemia
 Non-inferior to Amlodipine (Drugs 2007;67(3):393-405)
10
MorBidity-mortality EvAlUation of The I f
inhibitor Ivabradine in patients with coronary
disease and left ventricULar dysfunction
BEAUTIFUL Trial
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.
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).
 Ivabradine has established anti-ischemic and antianginal efficacy.
 In the large BEAUTIFUL trial, Ivabradine demonstrates that it reduces
coronary events in CAD patients.
 Objective
 To explore the effects of Ivabradine 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 Ivabradine
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.
Systolic Heart failure treatment with
the If inhibitor ivabradine Trial
SHIFT Trial
http://www.lancet.com published online August 29, 2010 DOI:10.1016/S0140-6736(10)61198-1
Background
 Elevated heart rate is associated with poor outcome in a
number of cardiovascular conditions including heart failure
 Heart rate remains elevated in many heart failure patients
despite treatment by beta-blockers
 Ivabradine is a novel heart rate-lowering agent acting by
inhibiting the If current in the sino-atrial node
 We hypothesized that the addition of ivabradine to
recommended therapy would be beneficial in heart failure
patients with elevated heart rate
Primary objective
To evaluate whether the If inhibitor ivabradine
improves cardiovascular outcomes
in patients with
1. Moderate to severe chronic heart failure
2. Left ventricular ejection fraction 35%
3. Heart rate 70 bpm and
4. Recommended therapy
Multinational study
Europe
Belgium
Germany
Portugal
Greece
Spain
Denmark
Ireland
Sweden
Finland
Italy
Turkey
France
The Netherlands
UK
Bulgaria
Czech Republic
Estonia
Hungary
Latvia
Lithuania
Norway
Poland
Russia
Slovakia
Slovenia
Ukraine
Romania
North America
Canada
Asia
China
South America
Argentina
Brazil
Chili
Hong Kong
India
South Korea
Malaysia
6505 patients, 37 countries, 677 centres
Australia
Inclusion criteria
 18 years
 Class II to IV NYHA heart failure
 Ischaemic/non-ischaemic aetiology
 LV systolic dysfunction (EF 35%)
 Heart rate 70 bpm
 Sinus rhythm
 Documented hospital admission for worsening heart failure
12 months
Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.
Study design
Ivabradine 5 mg bid
Ivabradine 7.5/5/2.5 mg bid according to
HR and tolerability
Screening
7 to 30 days
Matching placebo, bid
D0
D14
D28
3.5 years
Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.
M4
Every 4 months
Study endpoints
Primary composite endpoint
 Cardiovascular death
 Hospitalization for worsening heart failure
Other endpoints
 All-cause / CV / HF death
 All-cause / CV / HF hospitalization
 Composite of CV death, hospitalization for HF or non-fatal MI
 NYHA class / Patient & Physician Global Assessment
In total population and in patients with at least 50% target dose of beta-blockers
Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.
Patients and follow-up
7411 screened
6558 randomized
3268 to ivabradine
Excluded: 27
3290 to placebo
Excluded: 26
3241 analysed
3264 analysed
2 lost to follow-up
1 lost to follow-up
Median study duration: 22.9 months; maximum: 41.7 months
Baseline characteristics
Ivabradine
3241
Placebo
3264
60.7
60.1
Male, %
76
77
Ischaemic aetiology, %
68
67
NYHA II, %
49
49
NYHA III/IV, %
51
51
Previous MI, %
56
56
Diabetes, %
30
31
Hypertension, %
67
66
Mean age, y
Baseline characteristics
Ivabradine
3241
Placebo
3264
Mean heart rate, bpm
80
80
Mean LVEF, %
29
29
Mean SBP, mm Hg
122
121
Mean DBP, mm Hg
76
76
eGFR, mL/min/1.73 m2
75
75
Chronic HF background treatment
Patients (%)
100
90
89
90
91
91
84
Ivabradine
83
80
Placebo
70
61
59
60
50
40
30
22
22
20
10
3
4
0
Beta-blockers ACEIs and/or
ARBs
Diuretics
Aldosterone
antagonists
Digitalis
ICD/CRT
Background
beta-blocker treatment
Patients (%)
100
90
89
Ivabradine
89
Placebo
80
70
60
56
56
50
40
30
26
26
20
10
0
BB at
randomization
At least 50%
Target daily dose
target daily dose
Mean heart rate reduction
Mean ivabradine dose: 6.4 mg bid at 1 month
Heart rate (bpm)
90
6.5 mg bid at 1 year
Ivabradine
Placebo
80
80
75
75
70
67
64
60
50
0
2 weeks
1
4
8
12
16
Months
20
24
28
32
Primary composite endpoint
Ivabradine n=793 (14.5%PY)
Placebo n=937 (17.7%PY)
HR = 0.82 [95% CI 0.75-0.90] p<0.0001
Cumulative frequency (%)
40
Ivabradine
Placebo
- 18%
30
20
10
0
0
6
12
18
Months
24
30
Hospitalization for heart failure
Ivabradine n=514 (9.4%PY)
Cumulative frequency (%)
30
Placebo n=672 (12.7%PY)
HR = 0.74 [95% CI 0.66-0.83] p<0.0001
Ivabradine
Placebo
- 26%
20
10
0
0
6
12
18
Months
24
30
Cardiovascular death
Ivabradine n=449 (7.5%PY)
Cumulative frequency (%)
30
Placebo n=491 (8.3%PY)
HR = 0.91
p=0.128
18
24
Ivabradine
Placebo
20
10
0
0
6
12
Months
30
Effect of ivabradine on outcomes
Endpoints
Hazard ratio
95% CI
p value
Primary composite endpoint
0.82
[0.75;0.90]
p<0.0001
All-cause death
0.90
[0.80;1.02]
p=0.092
Death from HF
0.74
[0.58;0.94]
p=0.014
Hospitalisation for any cause
0.89
[0.82;0.96]
p=0.003
Hospitalisation for CV reason
0.85
[0.78;0.92]
p=0.0002
CV death/hospitalisation for HF
or non-fatal MI
0.82
[0.74;0.89]
p<0.0001
Effect of ivabradine in
prespecified subgroups
Test for interaction
Age
<65 years
≥65 years
Sex
Male
Female
Beta-blockers
No
Yes
Aetiology of heart failure
Non-ischaemic
Ischaemic
NYHA class
NYHA class II
NYHA class III or IV
Diabetes
No
Yes
Hypertension
No
Yes
Baseline heart rate
p=0.029
<77 bpm
≥77 bpm
0.5
1.0
Hazard ratio
Favours ivabradine
1.5
Favours placebo
Patients with at least 50% BB
target dose (n=3181)
Ivabradine
Primary composite
endpoint
Cardiovascular death
Hospitalisation for
worsening HF
Placebo
330
362
(11.9 PY)
(13.3 PY)
176
175
(5.9 PY)
(5.9 PY)
213
260
(7.7 PY)
(9.6 PY)
Hazard ratio
p value
0.90
ns
1.00
ns
0.81
p=0.021
0.5
1.0
Hazard ratio
Favours ivabradine
1.5
Favours placebo
NYHA class changes
Patients (%)
68
70
70
p=0.0003
60
Ivabradine
50
Placebo
40
30
28
24
20
10
5
6
0
Improvement
Stability
Worsening
Incidence of selected adverse
events (N = 6492)
Patients with an event
Ivabradine
Placebo
p value
N=3232, % (n)
N=3260, % (n)
All serious adverse events
45% (1450)
48% (1553)
0.025
All adverse events
75% (2439)
74% (2423)
0.303
Heart failure
25% (804)
29% (937)
0.0005
Symptomatic bradycardia
5% (150)
1% (32)
<0.0001
Asymptomatic bradycardia
6% (184)
1% (48)
<0.0001
Atrial fibrillation
9% (306)
8% (251)
0.012
Phosphenes
3% (89)
1% (17)
<0.0001
Blurred vision
1% (17)
<1% (7)
0.042
Conclusion
 Heart failure with systolic dysfunction and elevated heart rate
is associated with poor outcomes (primary composite endpoint
in the placebo group is 18%/year)
 Ivabradine reduced CV mortality or heart failure hospitalization
by 18% (p<0.0001). The absolute risk reduction was 4.2%
 This beneficial effect was mainly driven by a favourable effect
on heart failure death/hospital admission (RRR 26%)
 Overall, treatment with ivabradine was safe and well tolerated
ESC - 2012

Should be considered to reduce the risk of HF hospitalization in
patients in sinus rhythm with an EF ≤35%, a heart rate remaining ≥70
b.p.m., and persisting symptoms (NYHA class II–IV) despite treatment
with an evidence-based dose of beta-blocker (or maximum tolerated dose
below that), ACE inhibitor (or ARB), and an MRA (or ARB).
- IIa B

May be considered to reduce the risk of HF hospitalization in patients in
sinus rhythm with an EF ≤35% and a heart rate ≥70 b.p.m. who are unable to
tolerate a beta-blocker. Patients should also receive an ACE inhibitor (or ARB)
and an MRA (or ARB).
]
- IIb C
Autonomic Nervous System
60
61
Autonomic Nervous System
62