TERAPIA ANTISQUEMICA EN FALLA CARDIACA - Inicio 2015/charlascoronariaaguda... · TERAPIA...

TERAPIA ANTISQUEMICA EN FALLA

CARDIACA

JONATHAN POVEDA

FACC / FSCAI / FESC

2015

Systolic Heart failure treatment with

the If inhibitor ivabradine Trial

JONATHAN POVEDA

FACC / FSCAI / FESC

24 SET 1955

Dr. Paul Dudley White and Former President Dwight D. Eisenhower, 1963.

Messerli FH et al. N Engl J Med 2005;353:1205-1207.

Changes in the Management of Acute Coronary Syndromes since 1955.

Messerli FH et al. N Engl J Med 2005;353:1205-1207.

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

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.

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.

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.

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.

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)


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


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

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

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.

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

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

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.

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


3.5 years

Screening

7 to 30 days

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


In total population and in patients with at least 50% target dose of beta-blockers

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.

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


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

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 (%)


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


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


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


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


0 6 12 18 24 30

Months

30

20

10

0

Hospitalization for HF

- 26%


Placebo

Ivabradine

HR (95% CI), 0.74 (0.66–0.83),

p<0.0001


0 6 12 18 24 30

Months

30

20

10

0

Cardiovascular death


Placebo

Ivabradine

HR (95% CI), 0.91 (0.80–1.03),

p=0.128


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


Placebo

Ivabradine


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


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


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


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


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


last post randomisation value

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


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


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


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


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


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

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

Available now online from Lancet

http://www.lancet.com published online August 29, 2010 DOI:10.1016/S0140-6736(10)61198-1

MUCHAS GRACIAS!

TERAPIA ANTISQUEMICA EN FALLA CARDIACA - Inicio 2015/charlascoronariaaguda... · TERAPIA...

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