Lo mejor del Congreso ESC

2012 de Múnich

Lo mejor sobre insuficiencia

cardiaca (IC) Dr. JJ. Gómez Doblas

H.U. Virgen de la Victoria, Málaga

www.nejm.org

-1 -0.5 0.5 1 0

No IABP better

Sjauw et al. Eur Heart J 2009;30:459-468

IABP better

30-day mortality Risk difference

IABP n/N

No IABP n/N

-0.29 (-0.47 to -0.12)

Trial

No reperfusion

24/34

24/34

15/15

15/15

Moloupoulos

Overall

-0.18 (-0.20 to -0.16) Overall

Thrombolysis

Stomel

Kovack

Bengtson

Waksman GUSTO-1

SHOCK registry

NRMI-2 TT

28/51 10/27

48/99

11/20

30/62

220/439 1068/2180

1415/2878

10/13

13/19

58/101

17/21

146/248

300/417

2346/3501

2890/4320

Overall Overall

1049/2234 2488/5146

0.06 (0.03 to 0.10) -0.11 (-0.13 to -0.09)

Primary PCI NRMI-2 PCI

AMC CS

956/2035

93/199

401/955

26/93

427/1048 3332/5283

Background

MortalityIABP vs no IABP – Metaanalysis

Morta

lity

(%

)

Time after Randomization (Days)

Control IABP

41.3%

39.7%

30 20

P=0.92 by log-rank test

Relative risk 0.96; 95% CI 0.79-1.17; P=0.69 by Chi2-Test 10 0

40

Results

Primary endpoint study(30-Day mortality) 50

0 5 10 15 20 25 30

• The primary study endpoint results are supported

by a lack of benefit in secondary endpoints.

Summary+ Conclusions

• IABP support in cardiogenic shock is safe without

significant inherent complications.

• However, IABP support did not reduce 30-day

mortality in this large, randomized, multicenter trial in

cardiogenic shock patients complicating myocardial infarction

undergoing early revascularization

www.lancet.com

Background

Heart failure with preserved ejection fraction (HFpEF) accounts

for up to half of heart failure cases, and is associated with

substantial morbidity and mortality.

Pharmacologic therapies that have been tested in clinical trials

include beta-blockers, calcium-channel blockers, angiotensin

converting enzyme (ACE) inhibitors, and angiotensin receptor

blockers; to date no therapies have been shown to improve

clinical outcomes in this condition.

Several pathophysiologic mechanisms have been implicated in

this disorder, including abnormalities of diastolic function and

impaired natriuretic response to acute volume expansion.

LCZ696 – A First-in-Class Angiotensin

Receptor Neprilysin Inhibitor

4

Vasodilation

blood pressure

sympathetic tone

aldosterone levels

fibrosis

hypertrophy

Natriuresis/Diuresis

Inactive

fragments

NT-pro BNP

X Neprilysin

Natriuretic Peptide System pro-BNP

AT1 receptor X

Vasoconstriction

blood pressure

sympathetic tone

aldosterone

fibrosis

hypertrophy

(liver secretion) Angiotensin I

BNP

Angiotensin II

Renin Angiotensin System Angiotensinogen

NH

N

N N

N

O

OH

O

O

OH H N

O

H O

O

Valsartan AHU377

↓ LBQ657

Heart Failure

LCZ696

Objectives and Hypothesis

The PARAMOUNT trial was designed to test

the safety and efficacy of LCZ696 in patients

with HFpEF.

We hypothesized that LCZ696 would reduce

NT-proBNP to a greater extent than the ARB

valsartan at 12 weeks, and would be

associated with favorable changes in cardiac

structure and function at 36 weeks

Valsartan 160 mg, n=152 (100%) patients LCZ696 200 mg, n=149 (100%) patients

130 (87.2%) completed 12 weeks 131 (86.2%) completed 12 weeks

121 (81.2%) completed 36 weeks 120 (78.9%) completed 36 weeks

12-week double-blind main period

24-week double-blind extension period

Patient Flow 685 patients screened 308 patients randomized 7 patients excluded from analyses for

major GCP violations

Ch

ange

in L

eft

Atr

ial

Vo

lum

e (m

l)

NT

pro

BN

P (

pg/m

l)

Per

cent o

f P

atie

nts

Paramount: LCZ696 reduces NT-ProBNP at 12 weeks, and

Reverses Left atrial Remodeling and Improves NYHA Class at 36

weeks

Weeks Post Randomization

LCZ696

0 5 10 200

300

500 400

600

700

1000 900 800

LCZ696/Valsartan: 0.77 (0.64, 0.92) P = 0.005

p = 0.063

12

783 (670,914)

862 (733,1012) 835 (710, 981)

Valsartan

605 (512, 714)

12 Weeks 36 Weeks

-6

-5

-3

-4

-2

-1

2

1

0

LCZ696 Valsartan

P = 0.18 P = 0.003

LCZ696 Valsartan LCZ696 Valsartan 0

110 100

90

80

70

60

50

40

30

20

10

Week 12 Week 36

Change in NT-proBNP at 12 weeks Change in LA Volume

P = 0.11

Change in NYHA Class Worsened Unchanged Improved

P = 0.05

Solomon et al. Lancet 2012

Age ≥ 65 Age < 65 Female Male SBP > 140 SBP ≤ 140 eGFR ≥ 60 eGFR < 60 Diabetes (no) Diabetes (yes) EF ≥ 50 EF < 50 Atrial Fibrillation (no) Atrial Fibrillation (yes) Prior HF hospitalization (no) Prior HF Hospitalization (Yes) NYHA Class III NYHA class II NTproBNP ≤ median NTproBNP > median

0.1 0.2 0.4 0.6 0.8 1

Ratio NT-ProBNP LCZ696/Valsartan

P = 0.57 P = 0.69 P = 0.07 P = 0.18 P = 0.02 P = 0.49 P = 0.85 P = 0.62 P = 0.70 P = 0.57

n = 207 n = 59 n = 114 n = 152 n = 88 n = 178 n = 153 n = 109 n = 170

n = 96

n = 217

n = 31 n = 190 n = 76 n = 158 n = 108 n = 50 n = 214 n = 132

n = 134

Similar Treatment Effect in All Predefined Subgroups Interaction P-Value

Favors LCZ696 Favors Valsartan

NT

pro

BN

P (

pg/m

l)

0 5 10 15 20 25 30 35 40

Weeks Post Randomization

p = 0.005 p = 0.063

500

p = 0.20

400

LCZ696 300

200

Change in NT-proBNP over 36 weeks 1000 900

Valsartan 800 700

600

Ch

ang

e in

Blo

od

Pre

ssu

re (

mm

Hg

)

Blood Pressure Reduction

SBP DBP SBP DBP

-10

-2 -3 -4 -5 -6 -7 -8 -9

0 -1

LCZ696 VALSARTAN

12 weeks 36 weeks

P = 0.001 P = 0.09 P = 0.006 P = 0.001

Note: Change in BP correlated poorly with change in NT-proBNP (r = 0.104,

p=0.1). After adjustment for change in BP, the reduction in NT-proBNP

between groups remained statistically significant (p=0.01).

Conclusiones

We found that in patients with HFpEF, the angiotensin receptor

neprilysin inhibitor LCZ696 reduced NT-proBNP, a marker associated

with worse outcomes in HFpEF, to a greater extent than valsartan after

12 weeks of therapy. This reduction became evident at 4 weeks and was

sustained to 36 weeks, though the between group difference was no

longer significant.

We further observed a reduction in left atrial size, indicative of reverse

left atrial remodeling, and improvement in NYHA class in patients

randomized to LCZ696 after 36 weeks, compared with those randomized

to valsartan.

LCZ696 was well tolerated.

These hypothesis generating findings suggest that LCZ696 may have

beneficial effects in patients with HFpEF and that further testing of this

compound may be warranted in patients with this condition.

Disponible online

Randomizado, doble ciego, ensayo placebo-controlado en 6.505 pacientes

para evaluar la hipótesis de que reducir la FC con Ivabradina, inhibidor If,

mejora los eventos CV en pacientes con insuficiencia cardiaca crónica (IC)

Hospitalización por empeoramiento de la IC en los 12 últimos meses

previos a la randomización

FEVI 35%

Ritmo sinusal y FC 70 lpm

Recibiendo terapia de fondo basada en las guías

Diseño estudio

Swedberg K, et al. Lancet 2010;376: 875-885.

0 6 12 18 24 30

Meses

40

30

20

10

0

- 18%

Frecuencia cumulativa(%)

Placebo

Ivabradina

HR (95% CI), 0.82 (0.75–0.90)

p<0.0001

Swedberg K, et al. Lancet 2010;376: 875-885.

Objetivo primario: muerte CV o hospitalización por IC

0 6 12 18 24 30

Meses

30

20

10

0

Objetivo secundario preespecificado: Hospitalización por IC

- 26%

Hospitalización por IC (%)

Placebo

Ivabradina

HR (95% CI), 0.74 (0.66;0.83)

p<0.0001

Swedberg K, et al. Lancet 2010;376: 875-885.

Objetivo primario según la FC alcanzada a los 28 días en el grupo de Ivabradina

Lancet. Online 29-08-2010

Objetivo del presente análisis

• Evaluar el efecto de reducir la FC con Ivabradina

en las hospitalizaciones recurrentes por

empeoramiento de la IC

Principal razón de hospitalizaciones en pacientes con IC

= agravamiento de la IC

Elevada tasa de readmisión después de la primera

hospitalización:

• 20% al cabo de un mes

• 50% al cabo de 6 meses

• 17% son reingresados 2 o más veces

• Hospitalización = mayor contribución al coste del

tratamiento de la IC

Centers for Medicare and Medicaid Services. 2000 MedPAR data. DRG 127; Fonarow, GC. Rev Cardiovasc Med.

2002;3

(suppl 4):S3; Krumholz HM et al. R Arch Intern Med. 1997 Jan 13;157(1):99-104; Roger VL, Circulation.

2012;125(1):e2-e220.

Racional: carga de la

hospitalización por IC

Carga económica de la IC

Hospitalización está relacionada con los mayores costes

de la IC

Stewart S et al. Eur J Heart Fail 2002;4:361–71.

6% 5%

18%

69%

2%

Atención primaria

Outpatient referral

Fármacos

Visitas pacientes al alta

Hospitalizaciones

Características basales pre-

randomización

Nº de hospitalizaciones por IC durante el ensayo

Ninguna

(n=5319)

Una

(n=714)

Dos

(n=254)

3 o >

(n=218)

p-valor

Edad (años) 60.0 62.3 61.8 62.4 <0.0001

Sexo (%) 77 74 77 81 0.18

Fc (bpm) 79.3 82.2 83.4 82.2 <0.0001

PAS (mmHg) 122.3 119.8 118.1 117.6 <0.0001

PAD(mmHg) 76.0 75.0 73.4 73.3 <0.0001

FEVI (%) 29.3 27.6 27.8 27.1 <0.0001

NYHA clase II (%) 51 38 38 34 <0.0001

NYHA clase III/IV (%) 49 62 62 66

Duración de la IC (years) 3.3 4.2 4.3 4.6 <0.0001

Diabetes (%)

29 35 35 40 <0.0001

Borer J, Böhm M, Ford I, et al. Effect of ivabradine on recurrent hospitalization for worsening heart failure in patients with chronic systolic heart failure: the SHIFT study. Eur Heart J. 2012; doi:

10.1093/eurheartj/ehs259

Pre-randomización

tratamiento de fondo

Nº de hospitalizaciones por IC durante el ensayo

Ninguna

(n=5319)

Una

(n=714)

Dos

(n=254)

Tres o >

(n=218)

p-valor

Beta-bloqueantes (%) 90 89 80 86 <0.0001

IECAs y/o ARAII (%) 91 89 90 93 0.13

Antialdosterónicos (%) 58 69 67 73 <0.0001

Diuréticos (%) 82 90 90 95 <0.0001

Digitálicos (%) 20 30 33 35 <0.0001

Borer J, Böhm M, Ford I, et al. Effect of ivabradine on recurrent hospitalization for worsening heart failure in patients with chronic systolic heart failure: the

SHIFT study. Eur Heart J. 2012; doi: 10.1093/eurheartj/ehs259

0 6 12 18 24 30

Placebo

Ivabradina

40

10

0

IRR (95% CI), 0.75 (0.65;0.87)

P=0.0002

Incidencia cumulativa de hospitalizaciones por IC

(primera y repetidas)

Tiempo (meses)

20

30

- 25%

Efecto de Ivabradina en las hospitalizaciones totales por IC

Borer J, Böhm M, Ford I, et al. Effect of ivabradine on recurrent hospitalization for worsening heart failure in patients with chronic systolic heart failure: the

SHIFT study. Eur Heart J. 2012; doi: 10.1093/eurheartj/ehs259

Efecto de Ivabradina en las hospitalizaciones recurrentes por IC

Total-time approach

1.2 0.8 0.6 1.0 0.4

Favor ivabradina Favor placebo

Primera

hospitalización

Segunda

hospitalización

Tercera

hospitalización

Placebo (n=3264)

Ivabradina (n=3241)

Hazard

ratio

p-valor

p<0.001

p<0.001

p=0.012

514 (16%)

189 (6%)

90 (3%)

672 (21%)

283 (9%)

128 (4%)

0.75

0.66

0.71

Borer J, Böhm M, Ford I, et al. Effect of ivabradine on recurrent hospitalization for worsening heart failure in patients with chronic

systolic heart failure: the SHIFT study. Eur Heart J. 2012; doi: 10.1093/eurheartj/ehs259

Hospitalizaciones recurrentes por IC Gap-time approach = efecto en la 2º hospitalización

Tiempo desde la 1º hospitalización hasta la 2º hospitalización

Frecuencia cumulativa (%)

Placebo

Ivabradina

HR (95% CI), 0.84 (0.69–1.01)

P=0.058

12 6 24

0

0

10

20

30

40

50

60

70

Tiempo desde la 1º hospitalización (meses)

472 pacientes con al menos una primera y segunda

hospitalización por empeoramiento de la IC

Borer J, Böhm M, Ford I, et al. Effect of ivabradine on recurrent hospitalization for worsening heart failure in patients with chronic systolic heart

failure: the SHIFT study. Eur Heart J. 2012; doi: 10.1093/eurheartj/ehs259

Nº total de hospitalizaciones

Ivabradina

(N=3241)

Placebo

(N=3264)

IRR 95% CI p-valor

Hospitalización por

empeoramiento de la IC

902

1211 0.75

0.65-0.87

0.0002

Hospitalización por

cualquier causa

2661 3110

0.85 0.78-0.94

0.001

Hospitalización CV 1909

2272 0.84 0.76-0.94 0.002

Hospitalización por otra

causa que no sea

empeoramiento de la IC

1759 1899

0.92

0.83-1.02 0.12

Borer J, Böhm M, Ford I, et al. Effect of ivabradine on recurrent hospitalization for worsening heart failure in patients with chronic systolic heart failure:

the SHIFT study. Eur Heart J. 2012; doi: 10.1093/eurheartj/ehs259

La reducción de la FC con Ivabradina en pacientes con IC, ritmo sinusal,

con FC ≥70 lpm y ya tratados con las terapias que indican las guías reduce

de una manera substancial el riesgo de una deterioración clínica reflejada

por:

Reducción de las hospitalizaciones totales por empeoramiento de la IC

Reducción de la incidencia de las hospitalización recurrentes

Aumento del tiempo entre la primera y la hospitalización subsecuente

Este beneficio reduce la carga total del paciente con IC y puede reducir

substancialmente los costes en el sistema de salud

Conclusión

CRT Produces Long-term Improvements in

Disease Progression in Mildly

Symptomatic Heart Failure Patients:

Five-year results from the REsynchronization reVErses

Remodeling in Systolic left vEntricular dysfunction

(REVERSE) study

Cecilia Linde, MD, PhD, Stockholm, Sweden Michael R. Gold, MD, PhD, Charleston, U.S. William T. Abraham, MD, Columbus, U.S

Martin St John Sutton, MD, Philadelphia, U.S.

Stefano Ghio, MD, Pavia, Italy

Jeff Cerkvenik, MS, Minneapolis, U.S.

Jean-Claude Daubert, MD, Rennes, France

On Behalf of the REVERSE Study Group

Results of REVERSE main study

Primary Objective:

Clinical Composite Score

Powered Secondary Objective:

Change in LVESVi

Improved

P<0.01 Unchanged Worsened

P<0.10 Linde C, et al. JACC. 2008;52;1834-43

Purpose of present 5 years study

To evaluate if the benefits regarding :

Reverse remodeling, functional status, mortality

and HF hospitalizations are maintained over

5 years in the 419 pts assigned to CRT ON

Mea

n L

VE

F (

%)

Mea

n (

ml/

m2)

LV Reverse Remodeling

50

70 60

90 80

120 110 100

150 140 130

0 12 24 36 48 60 Months Since Randomization

-16

-25 -24 -22 -25

-19

-23 -22 -21 -24 -18

-15

20

24 22

26

30 28

36 34 32

0 12 24 36 48 60 Months Since Randomization

+4

+6 +6 +6 +6 +5

Error bars represent 95% confidence intervals

LVEF

Conclusions

CRT produced sustained reverse

remodeling accompanied by low mortality

and need for heart failure hospitalizations

Benefits of CRT persisted indicating that

CRT attenuates disease progression in

mildly symptomatic heart failure patients

with wide QRS over at least 5 years

The 2012 ESC heart failure guidelines

Main changes from 2008 guidelines: Treatment

1.

2.

3.

4.

5.

6.

An expanded indication for mineralocorticoid

(aldosterone) receptor antagonists (MRAs).

A new indication for the sinus node inhibitor

ivabradine.

An expanded indication for cardiac resynchronization

therapy (CRT).

New information on the role of coronary

revascularization in systolic HF.

Recognition of the growing use of ventricular assist

devices (VADs).

The emergence of transcatheter valve interventions.

Initial pharmacological therapy

Pharmacological therapy indicated in potentially all patients with systolic HF

ACE inhibitor

Beta-blocker

MRA

Pharmacological therapy – next step

Pharmacological therapy – other treatments with less certain benefits in systolic HF

Should be considered to reduce the risk of HF

hospitalization in patients in sinus rhythm with a heart

rate remaining ≥70 beats per minute 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).

Ivabradine

Caveat about EMA labelling: ≥75 b.p.m.

Recommendations for ivabradine: Patients NOT taking a beta-blocker

May be considered to reduce the risk of HF hospitalization

in patients in sinus rhythm with an EF ≤35% and a heart

rate remaining ≥70 beats per minute who are unable to

tolerate a beta-blocker. Patients should receive an ACE

inhibitor (or ARB), and an MRA (or ARB).

Recommendations for ivabradine: Patients with HF and angina: IA

Main changes from 2008 guidelines

1.

2.

3.

4.

5.

6.

An expanded indication for mineralocorticoid

(aldosterone) receptor antagonists (MRAs).

A new indication for the sinus node inhibitor

ivabradine.

An expanded indication for cardiac resynchronization

therapy (CRT).

New information on the role of coronary

revascularization in systolic HF.

Recognition of the growing use of ventricular assist

devices (VADs).

The emergence of transcatheter valve interventions.

When to consider CRT and ICD

Cardiac resynchronization therapy (CRT)

1.

2.

Expanded indication for patients with mild

symptoms

Less certain about patients

a) in atrial fibrillation b) with right bundle branch-block/IVCD

(non-LBBB)

An expanded indication for cardiac resynchronization therapy (CRT)

2 trials: MADIT-CRT and RAFT

Patients

All

RAFT

0.75 (0.64, 0.87)

MADIT-CRT

0.66 (0.52, 0.84)

LBBB

Non-LBBB

QRS < 150 QRS ≥ 150 QRS < 150 QRS ≥ 150

0.89 (0.60, 1.32) 0.51 (0.37, 0.69) 1.24 (0.70, 2.19) 0.83 (0.47, 1.47)

0.55 (0.35, 0.86) 0.41 (0.30. 0.56) 1.41 (0.85, 2.32) 0.92 (0.52, 1.64)

QRS morphology, duration and effect of CRT

CRT-D vs. ICD only HR for primary endpoint

New information on the role of coronary revascularization in systolic HF

Recognition of the growing use of ventricular assist devices (VADs) – Bridge to transplantation

Recognition of the growing use of ventricular assist devices (VADs) – Destination therapy

Lifestyle and non- pharmacological/ device/surgical interventions

Lack of robust evidence for most

lifestyle, non-pharmacological,

interventions e.g. sodium

restriction.

Lifestyle and non- pharmacological/ device/surgical interventions

Lo mejor sobre insuficiencia

cardiaca (IC) Dr. JJ. Gómez Doblas

H.U. Virgen de la Victoria, Málaga