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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