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TERAPIA ANTISQUEMICA EN FALLA
CARDIACA
JONATHAN POVEDA
FACC / FSCAI / FESC
2015
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Systolic Heart failure treatment with
the If inhibitor ivabradine Trial
JONATHAN POVEDA
FACC / FSCAI / FESC
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24 SET 1955
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Dr. Paul Dudley White and Former President Dwight D. Eisenhower, 1963.
Messerli FH et al. N Engl J Med 2005;353:1205-1207.
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Changes in the Management of Acute Coronary Syndromes since 1955.
Messerli FH et al. N Engl J Med 2005;353:1205-1207.
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HR decrease (at rest) versus other HR lowering agents
* 1 Weiss. 1993. 2 Frances. 1995.
**Tardif J-C, et al. 2005.
0
-5
-10
-15
, bpm
Ivabradine
** 5 mg bid 7.5 mg bid
Atenolol**
50 mg od 100 mg od
Diltiazem
* 200 & 300 mg od2
n=182
180-240 mg bid1
n=208 n=286 n=595 n=300
Effects of ivabradine on heart rate
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Ivabradine reduces heart rate in
patients already receiving β-blockers
54
56
58
60
62
64
66
68
Baseline M2 M4
Ivabradine
5 mg bid
Ivabradine 7.5 mg bid (90% of pts) or 5 mg bid (10%)
67
60 (- 7 bpm)
58 (- 9 bpm)
Ivabradine +
atenolol
atenolol
Placebo +
889 stable angina patients, 20 countries
Ivabradine
7.5 mg bid
Tardif JC, et al. Eur Heart J. 2009;30:540-548.
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Ivabradine + atenolol
Placebo + atenolol
0
10
20
30
40
50
60
Total exercise
duration
Time to limiting
angina
Time to angina
onset
Time to 1mm ST
segment
depression
P<0.001 P<0.001
P<0.001 P<0.001
Ivabradine increases all ETT parameters
in patients already receiving BBs further
*Evaluated at trough of drug activity
889 stable angina patients, 20 countries
Tardif JC, et al. Eur Heart J. 2009;30:540-548.
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BEAUTIFUL: Background
Double-blind, placebo controlled study (781 centers, 33 countries)
10 917 documented CAD patients with LVSD (EF < 40%)
Randomized to receive ivabradine or placebo on top
of optimal preventive therapy
Follow-up for 19 months
Fox K, et al. Lancet. 2008;372:807-816.
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Effect of ivabradine on primary
composite end point
HR (95% CI), 0.76 (0.58–1.00),
P=0.05
Years
HR (95% CI),
0.69 (0.47–1.01), P=0.06
Years
0
5
10
15
20
25
30
0 0.5 1 1.5 2
Eve
nt ra
te (
%)
0
5
10
15
20
25
30
0 0.5 1 1.5 2
Eve
nt ra
te (
%)
All angina patients Angina patients (HR >70 bpm)
24% 31% Placebo
Ivabradine
Placebo
Ivabradine
Composite of cardiovascular mortality or hospitalization
for fatal and nonfatal myocardial infarction or heart failure
Fox K, et al. Eur Heart J. 2009 FASTTRACK.
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Placebo
Ivabradine
HR (95% CI), 0.27 (0.11–0.66),
P=0.002
Years
Placebo
Ivabradine
HR (95% CI), 0.58 (0.37–0.92),
P=0.021
Years
0
5
10
15
0 0.5 1 1.5 2
Even
t ra
te (
%)
0
5
10
15
0 0.5 1 1.5 2
Even
t ra
te (
%)
42% 73%
Effect of ivabradine on hospitalization
for fatal/nonfatal MI
All angina patients Angina patients (HR >70 bpm)
Fox K, et al. Eur Heart J. 2009 FASTTRACK.
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Summary of the effects of
ivabradine on CV outcomes
0.05 24% Primary end point
0.51 12% CV death
0.02 42%
0.45 16% Hospitalization for HF
0.41 13% All-cause mortality
P value RRR
0.19 30% Coronary revascularization
Hospitalization for MI
0.06 31%
0.66 10%
0.002 73%
0.91 4%
0.40 17%
P value RRR
0.04 59%
All angina patients HR >70 bpm
Fox K, et al. Eur Heart J. 2009 FASTTRACK.
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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
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Fosbol et al. Int J Cardiol, 2010;140:279-286.
DIAMOND study; 1518 patients with HF post MI, 10 years follow up
P<0.0001
0 2 4 6 8 10
Years
1.0
0.8
0.4
0.0
0.6
0.2
> 91 bpm 81-91 bpm 71-80 bpm 40-70 bpm
Resting heart rate and mortality in HF post MI patients
Mortality
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Ivabradine: pure heart rate reduction
If inhibition reduces the diastolic depolarization slope, thereby lowering heart rate
RR
Pure heart rate reduction
0 mV
-40 mV
-70 mV
closed open
closed
Ivabradine
Thollon et al. Br J Pharmacol. 1994;112:37-42.
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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
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Europe Germany Portugal Belgium Greece Spain Denmark Ireland Sweden Finland Italy Turkey France The Netherlands UK
Bulgaria
Czech Republic
Estonia
Hungary
South America
Argentina
Brazil
Chili
North America
Canada
Asia
China
Hong Kong
India
South Korea
Malaysia
Australia
Latvia
Lithuania
Norway
Poland
Romania
Russia
Slovakia
Slovenia
Ukraine
Multinational study
6505 patients, 37 countries, 677 centres
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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
Inclusion criteria
Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.
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Study design
HR and tolerability Ivabradine 5 mg bid
Matching placebo, bid
Every 4 months D0 D14 D28 M4
Ivabradine 7.5/5/2.5 mg bid according to
Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.
3.5 years
Screening
7 to 30 days
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Study endpoints
Cardiovascular death
Hospitalisation for worsening heart failure
Primary composite endpoint
Other endpoints
All-cause / CV / HF death
All-cause / CV / HF hospitalisation
Composite of CV death, hospitalisation for HF or non-fatal MI
NYHA class / Patient & Physician Global Assessment
Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.
In total population and in patients with at least 50% target dose of beta-blockers
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Patients and follow-up
Median study duration: 22.9 months; maximum: 41.7 months
6558 randomized
3268 to ivabradine 3290 to placebo
3264 analysed 1 lost to follow-up
3241 analysed 2 lost to follow-up
7411 screened
Excluded: 27 Excluded: 26
Swedberg K, et al. Lancet. 2010;online August 29.
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Baseline characteristics
Ivabradine
3241
Placebo
3264
Mean age, y 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
Swedberg K, et al. Lancet. 2010;online August 29.
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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
Swedberg K, et al. Lancet. 2010;online August 29.
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Chronic HF background treatment
89 91
84
61
22
3
90 91
83
59
22
4
0
10
20
30
40
50
60
70
80
90
100
Beta-blockers ACEIs and/or ARBs
Diuretics Aldosterone antagonists
Digitalis ICD/CRT
Ivabradine
Placebo
Patients (%)
Swedberg K, et al. Lancet. 2010;online August 29.
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Background beta-blocker treatment
0
10
20
30
40
50
60
70
80
90
100
BB at
randomization
At least 50%
target daily dose
Target daily dose
89
56
26
89
56
26
Patients (%)
Ivabradine
Placebo
Swedberg K, et al. Lancet. 2010;online August 29.
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Main reasons for not achieving
Beta-blocker target dose, %
Ivabradine
n=2099
Placebo
n=2126
Hypotension 44 45
Fatigue 32 32
Dyspnea 14 14
Dizziness 13 12
Bradycardia 6 6
Main reasons for not
prescribing beta-blocker, %
Ivabradine
n=344
Placebo
n=341
COPD 37 32
Hypotension 17 20
Asthma 10 11
Cardiac decomp. 7 9
Fatigue 5 6
Background beta-blocker treatment
Swedberg K, et al. Lancet. 2010;online August 29.
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Mean heart rate reduction
70% of patients on ivabradine 7.5 mg bid
0 2 weeks 1 4 8 12 16 20 24 28 32
Months
90
80
70
60
50
67
75 75
80
64
Heart rate (bpm)
Placebo
Ivabradine
Swedberg K, et al. Lancet. 2010;online August 29.
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0 6 12 18 24 30
Months
40
30
20
10
0
Primary composite endpoint (CV death or hospital admission for worsening HF)
- 18%
Cumulative frequency (%)
Placebo
Ivabradine
HR (95% CI), 0.82 (0.75–0.90),
p<0.0001
Swedberg K, et al. Lancet. 2010;online August 29.
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0 6 12 18 24 30
Months
30
20
10
0
Hospitalization for HF
- 26%
Cumulative frequency (%)
Placebo
Ivabradine
HR (95% CI), 0.74 (0.66–0.83),
p<0.0001
Swedberg K, et al. Lancet. 2010;online August 29.
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0 6 12 18 24 30
Months
30
20
10
0
Cardiovascular death
Cumulative frequency (%)
Placebo
Ivabradine
HR (95% CI), 0.91 (0.80–1.03),
p=0.128
Swedberg K, et al. Lancet. 2010;online August 29.
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Death from heart failure
- 26%
0 6 12 18 24 30 Months
10
5
0
HR (95% CI), 0.74 (0.58–0.94),
p=0.014
Cumulative frequency (%)
Placebo
Ivabradine
Swedberg K, et al. Lancet. 2010;online August 29.
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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 heart failure 0.74 [0.58;0.94] p=0.014
Hospitalisation for any cause 0.89 [0.82;0.96] p=0.003
Hospitalisation for
cardiovascular reason
0.85 [0.78;0.92] p=0.0002
Cardiovascular death / hosp. for
HF or non-fatal MI
0.82 [0.74;0.89] p<0.0001
Swedberg K, et al. Lancet. 2010;online August 29.
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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 <77 bpm ≥77 bpm
Test for interaction
p=0.029
1.5 1.0 0.5 Hazard ratio
Favours ivabradine Favours placebo
Effect of ivabradine in prespecified subgroups
Swedberg K, et al. Lancet. 2010;online August 29.
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NYHA class changes
28
68
5
24
70
6
0
10
20
30
40
50
60
70
Improvement Stability Worsening
p=0.0003
Patients (%)
Ivabradine
Placebo
Swedberg K, et al. Lancet. 2010;online August 29.
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Patient Global Assessment
8
25
68
7
21
72
0 10 20 30 40 50 60 70 80
Worsening
Stability
Improvement
Patients (%)
p< 0.05
last post randomisation value
Ivabradine
Placebo
Swedberg K, et al. Lancet. 2010;online August 29.
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Physician Global Assessment
p= 0.001
9
34
57
8
31
61
0 10 20 30 40 50 60 70
Worsening
Stability
Improvement
Patients (%)
Ivabradine
Placebo
Swedberg K, et al. Lancet. 2010;online August 29.
last post randomisation value
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Mean heart rate reduction Patients with >50 % beta-blocker dose (n= 3181)
40
50
60
70
80
90
100
Mean HR in sinus rhythm (bpm)
79
63
67
Patients receiving at least half the target dose of beta-blockers
74 75
Placebo
Ivabradine
Swedberg K, et al. Lancet. 2010;online August 29.
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1.5 1.0 0.5
Hazard ratio
Favours ivabradine Favours placebo
Ivabradine Hazard ratio
Primary composite endpoint 330
(11.9 PY) 0.90 362
(13.3 PY)
Cardiovascular death 176
(5.9 PY) 1.00 175
(5.9 PY)
Hospital admission for worsening HF
213 (7.7 PY)
0.81 260 (9.6 PY)
Placebo
Patients with at least 50% BB target dose (n=3181)
p value
ns
ns
p=0.021
Swedberg K, et al. Lancet. 2010;online August 29.
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Incidence of selected adverse events (N = 6492)
Patients with an event
Ivabradine
N=3232, % (n)
Placebo
N=3260, % (n)
p value
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
Swedberg K, et al. Lancet. 2010;online August 29.
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Incidence of serious adverse events
Patients with an event
Ivabradine
N=3232, % (n)
Placebo
N=3260, % (n)
p value
All serious adverse events
Cardiac disorders
General disorders, administration conditions
Infection and infestations
Respiratory, thoracic, mediastinal disorders
Surgical and medical procedures
Gastrointestinal disorders
Neoplasm benign, malignant and unspecified
Renal and urinary disorders
Hepatobiliary disorders
Eyes disorders
45% (1450)
28% (920)
7% (240)
7% (216)
3% (107)
3% (102)
3% (89)
2% (68)
2% (51)
1% (29)
1% (18)
49% (1553)
30% (991)
8% (254)
7% (236)
4% (122)
4% (122)
3% (103)
2% (61)
1% (47)
1% (39)
<1% (13)
0.025
0.091
0.617
0.381
0.347
0.197
0.342
0.534
0.685
0.273
0.374
Swedberg K, et al. Lancet. 2010;online August 29.
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Patients with an adverse event,
leading to withdrawal
Ivabradine
N=3232, % (n)
Placebo
N=3260, % (n)
p value
All adverse events 14% (467) 13% (416) 0.051
Heart failure 2% (70) 3% (82) 0.367
Symptomatic bradycardia 1% (20) <1% (5) 0.002
Asymptomatic bradycardia 1% (28) <1% (5) <0.0001
Atrial fibrillation 4% (135) 3% (113) 0.137
Phosphenes <1% (7) <1% (3) 0.224
Blurred vision <1% (1) <1% (1) 1.000
Treatment discontinuation
Swedberg K, et al. Lancet. 2010;online August 29.
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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 cardiovascular mortality or heart failure
hospitalisation by 18% (p<0.0001). The absolute risk reduction
was 4.2%
This beneficial effect was mainly driven by a favourable effect
on HF death (26%) and hospitalisation for HF (26%)
Overall, treatment with ivabradine was safe and well tolerated
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Clinical implications
The addition of ivabradine to recommended
therapy significantly reduces death and
hospitalisations related to heart failure in patients
with heart rate 70 bpm
The NNT for 1 year to prevent …
One primary endpoint is 26
One hospitalisation for heart failure is 27
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Available now online from Lancet
http://www.lancet.com published online August 29, 2010 DOI:10.1016/S0140-6736(10)61198-1
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MUCHAS GRACIAS!