Lo mejor en insuficiencia cardiaca. #postACC16.

Lo mejor del Congreso ACC Chicago 2016
Lo mejor en insuficiencia cardiaca.
#postACC16.
Alfonso Valle
Hospital Marina Salud. Denia
@ValleAlfonso

Antes de empezar…

Otros debates

Dieta y ejercicio físico en IC
D.A.S.H. Diet PyramidMediterranean Diet Pyramid

IC y EJERCICIO FISICO (John Cleland )

Late Breaking Trials
IMPEDANCE HF
ixCELL-DCM Trial
INOVATE-HF
ATMOSPHERE
Otros estudios interés STICHES
PROMISE
VINDICATE

Non-invasive Lung IMPEDANCE-Guided Preemptive Treatment
in Chronic Heart Failure Patients: a Randomized Controlled
Trial (IMPEDANCE-HF trial)
Michael Kleiner Shochat, MD, BSc, PhDa, Avraham Shotan, MDa, David S Blondheim, MDa,
Mark Kazatsker, MDa,
Iris Dahan, MSITa, Aya Asif, MDa, Yoseph Rozenman, MDb, Ilia Kleiner, MDc, Jean Marc
Weinstein, MBBS, FRCPc,
Aaron Frimerman, MDa, Lubov Vasilenko, MDa, Simcha R Meisel, MD, MSca
aHeart Institute, Hillel Yaffe Medical Center, Hadera, Rappaport School of Medicine,
Technion, Haifa, Israel; bCardiovascular Institute, Wolfson Medical Center, Holon, Sackler
Faculty of Medicine, Tel-Aviv University, Israel, cCardiology Department, Soroka University
Medical Center, Beer Sheva.
IMPEDANCE-HF trial

IMPEDANCE-HF trial
Inclusion criteria:
CHF patients
Left ventricular EF ≤35%
New York Heart Association class II-IV
Total number of enrollees: 256
Duration of follow-up: 12 months
Mean patient age: 67 years
Percentage female: 20%
Lung fluid accumulation - without clinical signs
Ideal point to start preemptive treatment
Current point where treatment starts
Stable stage - There is no fluid accumulation in lung
Dramatic deterioration in patient’s condition & urgent hospitalization

Traditional Impedanc
Technique
TTI
Traditional Tech nologies VS RSMM Tech nology
EGM
TTI
IMPEDANCE-HF trial

Th e O b jective: Accurately Identif ying th e Lung
Imp edance (LI) Value
CWI1 Ω
X500~
CWI2 Ω
X500~
LI Ω X50~
A
Targ
et
Org
an
The Challenge:
Identifying small changes in the
Lung Impedance as 1-3 Ω
from the total TTI as 1050 Ω
Impossible
The Solution:
Elimination NOISE Chest Wall
Impedance (500 Ω+500 Ω)
from Transthoracic Impedance
(1050 Ω) makes identification
small changes in the Lung
Impedance Possible .
IMPEDANCE-HF trial
Transthoracic
Impedance
A-B (TTIAB) = + Lung Impedance + Chest Wall Impedance 2Chest Wall Impedance 1

IMPEDANCE-HF trial

Lung Impedance-guided treatment group
Control group treated by clinical assessment
1 year 2 year 3 year 4 year 5 year 6 year 7 year 8 year
Follow up period
P < 0.001
IMPEDANCE-HF trial
Rate of Hear t Failure h osp italizations ( p er patient*year)

IMPEDANCE-HF trial
Hospitalizations

IMPEDANCE-HF trial
Mortality

IMPEDANCE-HF trial
T A B L E Drug modifications during entire follow up
Medications Monitored Group Control Group p Monitoring /Control
group. Ratio of drug
adjustment
Rate of changes in medical therapy
Total 3166 (6.2)† 1244 (3.0)† <0.05 2.1 times
Diuretics 1530 (48%)‡ 515 (42%)‡ <0.05
Diuretics 1530 (3.0)† 515 (1.3)† <0.05 2.3 times
Beta Blockers 792 (25%)‡ 303 (24%)‡ <0.05
Beta Blockers 792 (1.6)† 303 (0.7)† <0.05 2.3 times
ACE inh /ARB 410 (13%)‡ 142 (11%)‡ <0.05
ACE inh /ARB 410 (0.8)† 142 (0.3)† <0.05 2.7 times
Nitrates 166 (5%)‡ 78 (6%)‡ <0.05
Nitrates 166 (0.3)† 78 (0.2)† <0.05 1.5 times
MRA 154 (5%)‡ 144 (12%)‡ NS
MRA 154 (0.3)† 144 (0.4)† NS 0.9 times
Digoxin 114 (4%)‡ 62 (5%)‡ <0.05
Digoxin 114 (0.2)† 62 (0.15)† <0.05 1.5 times

IMPEDANCE-HF trial
CONCLUSIONES
1. Reducción del 58% de ingresos por IC durante el primer año
2. . Reducción del 56% de ingresos por IC durante el seguimiento a 4
años.
7. Reduce mortalidad total un 43%
8. Reduce mortalidad cardiaca un 55% a 4 años
9. Reduce mortalidad por IC un 62% a 4 años
10. No cambios significativos en mortailidad no cardica
Hospitalizations (Secondary endpoint)
Deaths (Secondary endpoint)
3. Reduce toda causa de hospitalización un 39% a 4 años
4. Reduce ingreso de causa cardiológica un 52% a 4 años
5. Reduce ingreso no cardiológico un 9% durante 4 años de seguimiento
(p=0.6)
Hospitalizations (Primary endpoint)

IMPEDANCE-HF trial
LIMITACIONES
- Tamaño muestral reducido en solo dos centros
- Necesario nuevos estudios multicéntricos que validen resultados.
- Detalles del dispositivo: algoritmo, metodo de implante, coste, seguridad …
- Monitorización remota en IC con otrs dispositivos: the CardioMEMS HF System
(mide aumentos en PAP)

ixCELL-DCM Trial
Two-Week Expansion Increases:
1. CD45+ CD14+ M2-like macrophages
2. CD90+ MSCs
Potential Mechanisms:
1. Anti-Inflammatory
2. Tissue Remodeling
3. Endothelial Protection
4. Angiogenesis

ixCELL-DCM Trial
Phase 2b ixCELL–DCM Study Design
Design • Multicenter, randomized (1:1), double-blind, placebo-controlled phase 2b trial
Patient Population • NYHA Class III/IV ischemic dilated cardiomyopathy
Treatment • Intramyocardial ixmyelocel-T vs. placebo
Study Size • 126 patients randomized
• 114 patients treated at 28 centers in the United States
Primary Endpoints • Composite of all-cause death, CV hospitalization or outpatient treatment of acute
decompensated heart failure over 12 months
Key Secondary
Endpoints
• Win ratio
• LVEF and volumes by echo
• NYHA class
• Six-minute walk test

ixCELL-DCM Trial
Ixmyelocel-T
R
Placebo
Screening
Days -30 to -15
Randomization/Aspiration
Day -14
Injection
Day 1
Month 3 Month 6
Month 12
Data Analysis
Month 24
Safety Follow-up
12 Day ± 1 Expansion

ixCELL-DCM Trial

ixCELL-DCM Trial
CONCLUSIONES
1- Paciente tratado con ixmyelocel-T
presentan reducción significativa del
evento primario
2- No cambios en la FEVI o VTDVI,
NYHA or 6-minute-walk
3- Mejoría en eventos > mejoria
ecocardiográfica, son necesarios
más estudios para entender el
mecanismo del beneficio de ésta
terapia

INOVATE-HF
Insufficient
stimulation of
Parasympathetic
nervous system
Sympathetic
nervous
system
overdrive
Dual-Targeted Thoracic Spinal Cord Stimulation for HEArt
Failure as a Restorative Treatment

INOVATE-HF
Insufficient
stimulation of
Parasympathetic
nervous system
Sympathetic
nervous
system
overdrive
CardioFit® System Components
CardioFit Stimulation Lead:
• Multipolar recessed electrodes, coaxial lead, silicone body
• 4 Internal CUFF diameter sizes to accommodate variability
in vagus nerve:
• Designed for:
– Predominately unidirectional/efferent stimulation
– B fiber stimulation which is important for cardiac response
– Minimal current leakage to reduce side effects

INOVATE-HF
Insufficient
stimulation of
Parasympathetic
nervous system
Sympathetic
nervous
system
overdrive
Key Inclusion:
– Stable, NYHA class III on stable optimal
medical therapy (ACE-I /ARB, beta
blocker/CRT or other device therapy )
– LVEF ≤ 40% and LVEDD between 50 and 80
mm
– Predominately in sinus rhythm (unless
subject has predominately paced rhythm)
– Subjects with CRT devices may be included
in the trial provided they have had CRT for
at least 12 months with continued NYHA III
functional status (i.e. nonresponders)
Key Exclusion:
– 2nd or 3rd degree AV block or other pacemaker
indication not treated with a pacemaker
– Chronic (permanent) atrial fibrillation in past 3
months or hospitalized due to AF in past 6
months
– Uncontrolled Diabetes Mellitus
– Severe renal or hepatic failure
– History of stroke or TIA within 3 months prior to
enrollment, or significant neurological damage

INOVATE-HF
Insufficient
stimulation of
Parasympathetic
nervous system
Sympathetic
nervous
system
overdrive
• Design:
– Prospective, Randomized, multi-national, Controlled
– Open Label (device implant vs. OMT)
– Intent to treat analysis, starts with randomization
• Primary Endpoints:
– Efficacy: Time to first occurrence of “ unplanned heart failure
hospitalization or all cause death”
– Safety:
• 90 day system related complications
• Comparative non inferiority endpoint (time to first all
cause mortality or all cause complications through 1 year
excluding events in first safety objective)

INOVATE-HF
Insufficient
stimulation of
Parasympathetic
nervous system
Sympathetic
nervous
system
overdrive
PROTOCOLO

INOVATE-HF
Insufficient
stimulation of
Parasympathetic
nervous system
Sympathetic
nervous
system
overdrive
OBJETIVO PRIMARIO

INOVATE-HF
Insufficient
stimulation of
Parasympathetic
nervous system
Sympathetic
nervous
system
overdrive
OBJETIVO SECUNDARIO

INOVATE-HF
Insufficient
stimulation of
Parasympathetic
nervous system
Sympathetic
nervous
system
overdrive
SEGURIDAD
Objective
Performance
Criteria
LCB 75% (95% CI)
# pts with implant
attempt
# pts with procedure
related complications up
to 90 days
# pts at risk at 90 days % pts free of procedure
related complications for
90 days (95 % CI)
392 37 341 90.6% (87.7% - 93.5%)

CONCLUSIONES
1- Estimulación vagal es segura
2- NO REDUCE EVENTOS
3- No cambios eco
4- Mejora test marcha y QOL
INOVATE-HF

ATMOSPHERE
• Aliskiren added to enalapril is
superior to enalapril
• Aliskiren monotherapy is superior
to enalapril
• Aliskiren monotherapy is non-
inferior to enalapril
Non-inferiority
hypothesis
Superiority
hypotheses

ATMOSPHERE
• Age ≥18 years. NYHA class II-IV. LVEF ≤0.35
• BNP ≥150 pg/ml (NTpro-BNP ≥600 pg/ml) or if HF hosp.
within12 mo. BNP ≥100 pg/ml (NTpro-BNP ≥400 pg/ml)
• Background ACEi therapy equivalent to enalapril ≥10 mg/d
• Beta-blocker unless contraindicated/not tolerated
• SBP ≥95 mmHg run-in/ ≥90 mmHg at randomization
• eGFR ≥35 ml/min/1.73m2 at randomization /no decrease
>25% during run in
• Potassium <5.0 mmol/l run-in/ <5.2 mmol/l at randomization
CRITERIOS DE INCLUSION

ATMOSPHERE
TRIAL DESING
Median follow-up = 36.6 months4-12 weeks
Randomization
Double-blind
Primary outcome: CV death or heart failure hospitalization
(event driven: target 2318 patients [2369 accrued])
Open-label run-in
Prior ACEi use discontinued
Enalapril
5-10mg bid
Enalapril +
Aliskiren150mg qd
Enalapril 5-10mg bid* (n=2336)
Aliskiren 300mg qd† (n=2340)
Enalapril 5-10mg bid + Aliskiren300mg qd (n=2340)
*89% 10mg bid
†Target dose (titrated from 150mg qd)

ATMOSPHERE
CARACTERISTICAS BASALES
Aliskiren+Enalapril
(n=2340)
Aliskiren
(n=2340)
Enalapril
(n=2336)
Age (years) 63.2 ± 11.7 63.3 ± 12.1 63.3 ± 11.7
Women (%) 21.1% 22.7% 21.4%
Ischemic etiology (%) 57.1% 55.3% 55.7%
LVEF (%) 28.5 ± 5.7 28.4 ± 5.7 28.3 ± 5.7
NYHA class II / III (%) 64.0% / 33.7% 64.0% / 34.3% 61.7% / 36.3%
Systolic BP (mm Hg) 124 ± 19 124 ± 18 123 ± 18
Heart rate (beats/min) 72 ± 13 72 ± 12 72 ± 13
NT pro-BNP (pg/ml) 1193 (640-2351) 1167 (627-2173) 1223 (634-2194)
History of diabetes 28.4% 26.8% 27.9%
Digitalis 32.7% 32.0% 31.2%
Beta-blocker 92.0% 91.2% 91.9%
MRA 36.6% 36.9% 37.8%
CRT-P/CRT-D 6.1% 5.1% 5.6%
ICD/CRT-D 15.0% 15.5% 14.4%

ATMOSPHERE
DIABETICOS
• Following the results of ALTITUDE (aliskiren added to an ACE-I/ARB in patients
with diabetes and CKD/CVD) and ASTRONAUT (aliskiren added to an ACE-I/ARB
in patients hospitalized with HF), the Clinical Trials Facilitation Group of the
Heads of Medicines Agencies in Europe requested that patients with diabetes
have study drug discontinued.
• Median follow-up for analysis of efficacy in patients with diabetes was 24.1
months and in patients without diabetes was 46.0 months.

ATMOSPHERE
OBJETIVO PRIMARIO
cardiovascular death or heart
failure hospitalization

ATMOSPHERE
OBJETIVO SECUNDARIO
HF hospitalizationCV death

ATMOSPHERE
• Aliskiren monotherapy is non-
inferior to enalapril
Non-inferiority
hypothesis
Aliskiren
(n=2340)
Enalapril
(n=2336)
HR
(95% CI)
P value
All patients
n (%)
791
(33.8%)
808
(34.6%)
0.99
(0.90-1.10)
0.0184*
*Did not meet the pre-specified P-value for significance
Pre-specified criterion for declaring non-inferiority was a P-value
≤0.0123 (one-sided)

ATMOSPHERE

ATMOSPHERE
CONCLUSIONES
Terapia combinada
1- Combinación ALK+ENL no tiene
beneficio clínico y si + efectos
secundarios
2- Doble Bloqueo SRAA: via
muerta?
Aliskiren vs ENL
3- No alcanza el criterio de no
inferioridad

Late Breaking Trials
IMPEDANCE HF
ixCELL-DCM Trial
INOVATE-HF
ATMOSPHERE
Otros estudios interés STICHES
VINDICATE
PROMISE

STICHES

STICHES
CRITERIOS DE INCLUSIÓN
Randomization
1,212 Subjects
Randomized
MED
n = 602
CABG + MED
n = 610

STICHES
• Age (median) 60 years; 12% women
• Prior MI 77%; Diabetes 39%
• Baseline NYHA II-IV 89%
• LVEF 28% and ESVI 78 ml/m2 (median)
• Multi-vessel disease 74%; Proximal LAD 68%
Randomization
1,212 Subjects
Randomized
MED
n = 602
CABG + MED
n = 610
PROTOCOLO
2º rama: 1.000 pacientes + disfunción , aleatorizados a cirugía sin
(n=499) o con (n=501) técnicas de restauración ventricular

STICHES
RESULTADOS
- CABG extended median survival by 18 months
compared to medical therapy alone
- CABG prevented one death for every 14
patients treated.
Muerte por cualquier causa
CABG:58,9%
TMO: 66,1%;
HR 0,84 [IC 95% 0,73-0,97]
p=0,02

CV mortality: 40.5% vs. 49.3%, HR = 0.79, 95% CI 0.66-0.93; p = 0.006);
All-cause mortality or MI: 61.6% vs. 67.9%, p = 0.03.
STICHES
2º rama:
- mayor reducción del volumen telediastólico ventricular (-19% vs. -6%; p<0,001),
- variable mortalidad global u hospitalización de causa cardiaca (58% vs. 59%; p=0,9) 4 años

MED (N=602) CABG (N=610)
Medication Baseline
Last
Follow-Up Baseline
Last
Follow-Up
Aspirin 513 (85) 466 (82) 489 (80) 449 (82)
Aspirin or clopidogrel 533 (89) 486 (86) 509 (83) 467 (85)
ACE inhibitor or ARB 531 (88) 483 (85) 554 (91) 456 (83)
Beta-blocker 529 (88) 500 (88) 507 (83) 477 (87)
Statin 500 (83) 478 (84) 483 (79) 471 (86)
Loop Diuretics 392 (65) 400 (71) 399 (66) 404 (73)
K+ Sparing Diuretics 276 (46) 300 (53) 280 (46) 297 (54)
STICHES

STICHES
- En pacientes con MCD ISQUÉMICA, la terapia médica + CABG presentó mayor
mortalidad a los 30 días, pero con una mejora significativa de la mortalidad a largo
plazo (a 10 años) en comparación con el tratamiento médico solo.
- NNT: 14 pacientes necesitan ser tratados con CABG para salvar una vida
- Técnicas de restauración ventricular no aporta beneficio clínico.
- Hacer estudio angiográfico debe ser obligatorio en un paciente con disfunción
ventricular
- Validez externa?: condición del mismo que los cirujanos participantes tuvieran
reportada una mortalidad operatoria <5% en la población similar la del estudio

Total (n=163) Placebo (n=83) Vitamin D (n=80)
6 Minute walk test 292.9 (120.35) 283.7 (116.84) 302.2 (123.81)
LVEF (%) 26.1 (10.68) 26.5 (10.62) 25.6 (10.80)
LVEDD (mm) 57.8 (7.58) 58.0 (6.49) 57.6 (8.62)
LVESD (mm) 50.3 (8.50) 50.7 (7.58) 49.8 (9.42)
LVEDV (mls) 163.0 (66.60) 164.1 (60.07) 161.8 (73.58)
LVESV (mls) 115.4 (59.39) 119.4 (53.30) 111.0 (63.58)
25(OH) Vitamin D (nmol/L) 37.3 (22.56) 36.4 (20.24) 38.2 (24.81)
Parathyroid hormone (pmol/L) 11.4 (8.09) 11.7 (7.50) 11.0 (8.75)
Creatinine (μmol/L) 96 (29.3) 94.4 (29.42) 96.6 (29.26)
VINDICATE
Endpoint
Ancova
Difference in mean change p-value
Six minute walk distance (m) -24.11 [-65.81, 17.60] 0.255
LVEF (%) 6.07 [3.20, 8.94] <0.001
LVEDD (mm) -2.49 [-4.09, -0.90] 0.002
LVESD (mm) -2.09 [-4.11, -0.06] 0.043
LVEDV (mls) -13.11 [-25.63, -0.60] 0.040
LVESV (mls) -12.65 [-24.76, -0.54] 0.041

CONCLUSIONES
- Nivel Vitamina D suele
ser bajo en paciente con
IC
- 1 año de tratamiento
con suplemento vitD3 es
seguro
- 1 año con dosis alta de
vit D3 presenta
beneficios en el
remodelado V
VINDICATE
Witte et al JACC 2016

Método
Patients randomized (N=10,003)
Tested as randomized with interpretable results
(N=8966; 90%)
Stress
Nuclear
(N=1704; 71%)
Stress
Echo
(N=505; 21%)
Exercise
ECG
(N=179; 8%)
Stress
Nuclear
(N=1362; 66%)
Stress
Echo
(N=465; 22%)
Exercise
ECG
(N=251; 12%)
Women (N=4720; 53%) Men (N=4246; 47%)
CTA
(N=2332; 49%)
Stress
(N=2388; 51%)
CTA
(N=2168; 51%)
Stress
(N=2078; 49%)
Exclusions: N=1037 (10%)
Not tested as randomized:
N=366 (35%)
Indeterminate test result:
N=661 (65%)
PROMISE

Resultados en MUJER
7.9%
2.4%
11.5%
2.3%
0
5
10
15
Positive Test Clinical Event
%ofPatientsinEachTestingArm
CTA Stress
9.8%
5.1%
1.8% 1.9%
0
5
10
15
CTA Stress
EventRate(%)
Positive Test Negative Test
n = 184 274 57 55 n = 18 39 14 41
+
- + -
P = 0.041
P < 0.001
La probabilidad de test + con TC < test estrés, en cambio un TC + tiene VPP > estres en
predicción de eventos
PROMISE

Resultados en HOMBRES
El TC tiene > % de positivos. Un TC+ = estrés en predicción de eventos
16.1%
3.7%
14.0%
3.5%
0
5
10
15
20
Positive Test Clinical Event
%ofPatientsinEachTestingArm
CTA Stress
8.9%
11.4%
2.7% 2.2%
0
5
10
15
20
CTA Stress
EventRate(%)
Positive Test Negative Test
+
P = 0.309
P = 0.047
+
PROMISE

CONCLUSIONES
1- Mujer:
Prob +: TC < estrés.
VPP: TC+
2- Hombre:
Prob +: TC > estrés.
VPP: TC=estrés
Mujer – test isquemia: TC
Varón – resultados similares
PROMISE

CONCLUSIONES EN IC
1- IMPEDANCIA TORÁCICA: otra vez a medir?
2- ESTIMULACIÓN VAGAL: de momento….. Mejor medir impedancia
3- CEL MADRE:
la promesa que siempre aparece.
mecanismo de mejora?
4- ALISKIREN
….. Sigamos midiendo impedancia
no bloquear SRAA en varios niveles
5- MIOCARDIOPATIA DILATADA
siempre coronariografía
valorar opción de CABG si EC: reduce mortalidad. NNT 14
6- VIT D: déficit habitual. Dosis diaria mejora remodelado VI
7- TEST DE ISQUEMIA por sexo?
en hombres el que sea
mujer: la mejor opción el TC

…..Y si no fueras cardiólogo?
#PostACC16

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Lo mejor en insuficiencia cardiaca. #postACC16.

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