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Dr. Marcelo Llancaqueo ValeriDepartamento de Cardiología
Clínica Las Condes
Actualización del tratamiento
farmacológico de la insuficiencia
cardíaca con fracción de eyección
disminuida
1
Epidemiologia de la Insuficiencia
CardiacaEstadística Enf CV – Stroke Update 2014 Circulation 2014;129: e28-e292
Población Prevalencia
(> 20 a) 2010
Incidencia
(> 45 a)
2010
Mortalidad
2010
Altas
Hospitalaria
2010
Costos
Global 5,1 mill (2,1%) 825.000 57.757 1.023.000 $30,7
billones
Hombres 2,7 mill (2,5%) 395.000 24.385
(42,2%)
501.000
Mujeres 2,4 mill (1,8%) 430.000 33.372
(57,8%)
522.000
Proyección
2030 USA
8 mill $ 69,7
billones
3
Morbilidad y Mortalidad:
arritmias, falla bomba
Sintomas IC:
dIsnea, edema, fatiiga
Fisiopatología IC FE reducida
Remodelación Maladaptiva
y
progresiva disfunción VI
Alteraciones Hemodinamicas
retencion Na - Agua
Hiper Activacion Neurohormonal (SRAA- Simpatico)
Daño Cardiomiocitos y matriz extracelular
Cambios Morfo-funcionales del Miocardio y estres parietal del VI
Vasoconstricion, fibrosis, apoptosis, hipertrofia,
alteraciones moleculares y celulares: Miotoxicidad
McMurray. N Engl J Med 2010;362:228–38; Francis et al. Ann Intern Med 1984;101:370–7; Krum, Abraham. Lancet 2009;373:941–55
Terapia IC con FE reducida
Asintomatico CF I CF II CF III CF IV
IECADisf VI FE ≤ 40% y C
Coronaria
ARA 2
ß bloqueadores Coronarios
Antagonista
Aldosterona
post IAM FE ≤
40% y DM
Hidralazina
Nitritos
Digoxina FA FA FA - RS FA - RS
Diuréticos solo para sintomas congestivos
TAC Oral FA, Trombo intracavitarios, AVE isquemico, FE muy baja?
5
Hiper activación SRAA y Simpatico
SNS
SRAA
VasoconstriccionPresion Arterialtono Simpatico
AldosteronaHipertrofia
Fibrosis
Ang II AT1R
HFrEF
SIMPTOMAS &
PROGRESION
Epinephrine
Norepinephrineα1, β1, β2
receptors
VasoconstriccionSRAA actividad
VasopresinaFrec CardiacaContractilidad
inhibitors SRAA
(IECA, ARAB, MRA)
β-bloqueadores
1. McMurray et al. Eur Heart J 2012;33:1787–847;
Figure references: Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; Kemp & Conte. Cardiovascular Pathology 2012;365–371;
Schrier & Abraham. N Engl J Med 1999;341:577–85
El bloqueo del SRAA es de vital importancia en la terapia de la ICFER: Efectos evidentes para IECA-ARA2 y AA1
Beneficios de β-bloqueadores, tambien son evidentes1
Β- bloqueoAntagonista
Mineralocorticoides
Drogas que reducen la Mortalidad en
Insuficiencia Cardiaca con FE reducida
IECAARA2
Drogas que inhiben SRAA
10%
20%
30%
40%
0%
% D
ism
inu
ció
n
Mo
rtalid
ad
1. McMurray et al. Eur Heart J 2012;33:1787–847; 2. SOLVD Investigators. N Engl J Med 1991;325:293–302;
3. CIBIS-II Investigators. Lancet 1999;353:9–13; 4. Pitt et al. N Engl J Med 1999;341:709-17;–50;
5. Granger et al. Lancet 2003;362:772–6; 6. Go et al. Circulation 2014;129:e28-e292;
7. Yancy et al. Circulation 2013;128:e240–327; 8. Levy et al. N Engl J Med 2002;347:1397–402
Insuficiencia Cardiaca Disfunción Sistólica
Si Persiste CF II-IV
Antagonistas Aldosterona
SI persiste CF II-IV
FE< 35% y FC > 70
Ivabradina
SI persiste CF II-IV
FE < 35%
QRS > 120 meg
TRV -DAI
Diuréticos para reducir la congestión
IECA/ARA2 - BB
SI persiste sintomático CF II-IV: Digoxina – Hidralazina – Isosorbide
Asistencia Ventricular - Tx Cardiaco
Guía Europea de Insuficiencia Cardiaca 2012
Heart Failure Guidelines. European Society of Cardiology
Problemas no completamente Resueltos en IC
I Cardiaca
Congestión
Inotropismo
Metabolismo
Vasodilatación
Objetivos Terapéuticos en estudio en IC
Hiper activación SRAA y Simpático
SNS
SRAA
VasoconstricciónPresión Arterialtono Simpatico
AldosteronaHipertrofia
Fibrosis
Ang II AT1R
HFrEF
SIMPTOMAS &
PROGRESION
Epinephrine
Norepinephrineα1, β1, β2
receptors
VasoconstricciónSRAA actividad
VasopresinaFrec CardiacaContractilidad
inhibitors SRAA
(IECA, ARA2, MRA)
β-bloqueadores
Sistema peptidos
Natriureticos
VasodilataciónPresión ArterialTono SimpaticoNatriuresis/diuresisVasopresinaAldosteroneFibrosisHipertrofia
NPRs NPs
1. McMurray et al. Eur Heart J 2012;33:1787–847;
Figure references: Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; Kemp & Conte. Cardiovascular Pathology 2012;365–371;
Schrier & Abraham. N Engl J Med 1999;341:577–85
El bloqueo del SRAA es de vital importancia en la terapia de la ICFER: Efectos evidentes para IECA-ARA2 y AA1
Beneficios de β-bloqueadores, también son evidentes1
PARADIGM-HF: Pacientes
10,513 patients entered enalapril run-in phase (median duration, 15 days; interquartile range [IQR], 14–21)
9419 entered LCZ696 run-in phase(median duration, 29 days; IQR, 26–35)
8442 underwent randomization
4187 were assigned to receive LCZ696
4176 had known final vital status
11 had unknown final vital status
4212 were assigned to receive enalapril
4203 had known final vital status
9 had unknown final vital status
1102 discontinued study:
591 (5.6%) had adverse event
66 (0.6%) had abnormal laboratory or other test result
171 (1.6%) withdrew consent
138 (1.3%) had protocol deviation, administrative
problem or were lost to follow-up
49 (0.5%) died
87 (0.8%) had other reasons
977 discontinued study:
547 (5.8%) had adverse event
58 (0.6%) had abnormal laboratory or other test result
100 (1.1%) withdrew consent
146 (1.6%) had protocol deviation, had administrative
problem, or were lost to follow-up
47 (0.5%) died
79 (0.8%) had other reasons
43 were excluded:
6 did not undergo valid randomization
37 were from four sites prematurely closed because
of major Good Clinical Practice violations
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.
LCZ696
(n=4187)
Enalapril
(n=4212)
Hazard
Ratio
(95% CI)
P
Value
Primary
endpoint
914
(21.8%)
1117
(26.5%)
0.80
(0.73-0.87)0.0000002
Cardiovascular
death
558
(13.3%)
693
(16.5%)
0.80
(0.71-0.89)0.00004
Hospitalization
for heart
failure
537
(12.8%)
658
(15.6%)
0.79
(0.71- 0.89)0.00004
PARADIGM-HF: LCZ696 vs Enalapril on
Caracteristicas basales y Punto Final Primario
(Muerte CV – Hospitalización IC)
LCZ696
(n=4187)
Enalapril
(n=4212)
Age (years) 63.8 ± 11.5 63.8 ± 11.3
Women (%) 21.0% 22.6%
Ischemic cardiomyopathy (%) 59.9% 60.1%
LV ejection fraction (%) 29.6 ± 6.1 29.4 ± 6.3
NYHA functional class II / III (%)
71.6% / 23.1% 69.4% / 24.9%
Systolic blood pressure (mm Hg)
122 ± 15 121 ± 15
Heart rate (beats/min) 72 ± 12 73 ± 12
N-terminal pro-BNP (pg/ml)1631 (885-
3154)1594 (886-3305)
B-type natriuretic peptide (pg/ml)
255 (155-474) 251 (153-465)
History of diabetes 35% 35%
Digitalis 29.3% 31.2%
Beta-adrenergic blockers 93.1% 92.9%
Mineralocorticoid antagonists
54.2% 57.0%
ICD and/or CRT 16.5% 16.3%27 meses seguimiento
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.
LCZ696
(n=4187)
Enalapril
(n=4212)
P
Value
Prospectively identified adverse events
Symptomatic hypotension 588 388 < 0.001
Serum potassium > 6.0 mmol/l 181 236 0.007
Serum creatinine ≥ 2.5 mg/dl 139 188 0.007
Cough 474 601 < 0.001
Discontinuation for adverse event 449 516 0.02
Discontinuation for hypotension 36 29 NS
Discontinuation for hyperkalemia 11 15 NS
Discontinuation for renal impairment 29 59 0.001
Angioedema (adjudicated)
Medications, no hospitalization 16 9 NS
Hospitalized; no airway compromise 3 1 NS
Airway compromise 0 0 ----
PARADIGM-HF: Efectos Adversos
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.
Omecamtiv Mecarbil (OM) es un Novel Activador Selectivo Miosina Cardiaca
Malik FI, et al. Science 2011; 331:1439-43.
Mechanochemical Cycle of Myosin
Force production
Omecamtiv mecarbil increases the entry rate of myosin into the
tightly-bound, force-producing state with actin
“More hands pulling on the rope”
Increases duration of systole
Increases stroke volume
No increase in myocyte calcium
No change in dP/dtmax
No increase in MVO2
Results of ARTS-HF: finerenone versus eplerenone in patients with worsening chronic heart failure and diabetes and/or chronic kidney disease
Gerasimos Filippatos
Finerenone (BAY 94-8862) analogo no steroidal AntagonistaReceptores de Aldosterona, con mayor selectividad al recptor
que Espironolactona y mayor afinidad que Eplerenona1
Change in health-related quality of life
Error bars show standard deviations
Mea
n c
han
ge f
rom
bas
elin
e in
To
tal S
ymp
tom
sco
re
60
30
20
10
–10
24.321.3
24.5
29.3
28.3 22.2
Kansas City Cardiomyopathy Questionnaire
40
50
0
Eplerenone(n = 143)
Finerenone2.5–5 mg(n = 116)
Finerenone5–10 mg(n = 117)
Finerenone7.5–15 mg(n = 120)
Finerenone10–20 mg(n = 128)
Finerenone15–20 mg(n = 118)
Patiromer
- La Hiper K+ es una complicación
frecuente en el manejo del
bloqueo SRAA en pacientes con
IRC y DM o IC
- Polimero no absorbible que
intercambia K+ por Ca+
- Paciente de 18 a 80 años
- IRC etapa 3-4 (VFG 15 a 60 ml)
- Kalemia mayor 5,5 a 5,8 y >5,8
OPAL-HK Investigators* N Engl J Med 2015; 372:211-221
The SOCRATES (SOluble guanylate Cyclase
stimulatoR in heArT failurE Studies)
Vericiguat
• Activación de la GMPc
• Genera vasodilatación
independiente de ON
• Estudio Fase 2
• 456 Pacientes
• FE reducida
JAMA. 2015 Dec 1;314(21):2251-62.
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