Presentación utilizada por el Dr. Domingo Pascual Figal en el directo online ‘Lo mejor en Insuficiencia Cardiaca de ESC Múnich 2018’, realizado el 19 de septiembre de 2018 en la Casa del Corazón

2.  Epidemiología
 Transición tras hospitalización
 IC preservada
 Comorbilidades
 Metanálisis y vida real
 Redefinición de daño miocárdico

3. PATIENTS’ JOURNEY OF CARE FOLLOWING INCIDENT HF:
diagnostic test, treatments and care pathways in 93,000 patients
Conrad N, et al. Lancet. 2018; 391: 572-580

4. Conrad N, et al. Lancet. 2018; 391: 572-580
PATIENTS’ JOURNEY OF CARE FOLLOWING INCIDENT HF:
diagnostic test, treatments and care pathways in 93,000 patients

5. Conrad N, et al. Lancet. 2018; 391: 572-580
PATIENTS’ JOURNEY OF CARE FOLLOWING INCIDENT HF:
diagnostic test, treatments and care pathways in 93,000 patients

6. CLCZ696B2401 study
A multicenter, randomized, open label, parallel group study comparing
Two modalities of tReatment with LCZ696 in heArt failure patieNtS with
reduced ejectIon-fracTion hospItalized for an acute decOmpensation
eveNt (ADHF) - the TRANSITION study

7. Data on-file

8. Session Title Date & Time
Poster Session 1:
Chronic heart failure –
Pathophysiology and
mechanisms
Poster # P886
Initiation of sacubitril/valsartan in hospitalized patients with
heart failure with reduced ejection fraction after
hemodynamic stabilization:
primary results of the TRANSITION study
Sat 25 Aug
11:00-16:00
Poster Session 7:
Chronic heart failure –
Treatment
Poster # P6531
Initiation of sacubitril/valsartan in hospitalized patients with
HFrEF after hemodynamic stabilization: baseline
characteristics of the TRANSITION study compared with
TITRATION and PARADIGM-HF
Tue 28 Aug
14:00-18:00
TRANSITION Investigators in Munich:
10 weeks results presentation and discussion
Sat 25 Aug
06:45-08:15am

9. Life-time risk after a first hospitalization ADHF
Median time from hospital discharge
Readmissionrate
Initial
discharge Death
Transition phase
Plateau
phase
Palliation and priorities
Picture from: Desai AS and Stevenson LW. Circulation. 2012; 126(4): 501-506

10. Key eligibility criteria for TRANSITION,
PARADIGM-HF and TITRATION studies
Variable TRANSITION PARADIGM-HF TITRATION
Age ≥18 years
NYHA class II-IV
LVEF ≤40% ≤40%a ≤35%
Plasma BNP or
NT-proBNP
levels
No pre-defined
entry levels
(BNP ≥150 pg/mL or NT-proBNP
≥600 pg/mL) or
(BNP ≥100 pg/mL or NT-proBNP
≥400 pg/mL and hospitalization for
HF within last 12 months)
No pre-defined
entry levels
SBP ≥110 mmHg ≥100 mmHg ≥100 mmHg
eGFR ≥30 mL/min/1.73 m2
Clinical status Inpatients Outpatients
Inpatients and
outpatients
Previous
ACEI/ARB dose
Variable doses of
ACEI/ARB or
treatment naïveb
Stable dose of an ACEI/ARB
equivalent to enalapril 10 mg/day for
at least 4 weeks before the
screening
Variable doses of
ACEI/ARB or
treatment naïveb,c
ACEI, angiotensin-converting enzyme inhibitor; ARB,
angiotensin receptor blocker; BNP, B-type natriuretic
peptide; eGFR, estimated glomerular filtration rate; HF,
heart failure; LVEF, left ventricular ejection fraction; NYHA,
New York Heart Association; NT-proBNP, N-terminal pro-
B-type natriuretic peptide; SBP, systolic blood pressure
a LVEF eligibility criteria was changed to ≤35% in a protocol
amendment; b ACEI/ARB naïve defined as patients without
any previous ACEI/ARB for ≥4 weeks before hospital
admission; c For outpatients, ACEI/ARB dose must have
been stable for at least 2 weeks
Clinicaltrials.gov identifier: NCT02661217. ESC Congress, Munich, 2018. P6531

11. TRANSITION:
Flexibility similar to the clinical practice
HF treatment optimization in hospitalized patients with HFrEF
stabilized after an ADHF event*
Optimization of
guidelines
recommended HF
therapies* at the
discretion of the
investigator
Recruiting hospitalized
HFrEF patients:
• On any dose of
ACEI/ARB
• Naive to ACEI/ARB
• De novo = newly
diagnosed
Up-titration and down-
titration of
sacubitril/valsartan
according to patient
tolerability
*Beta-blockers, MRAs, and replacement of ACEi/ARB by sacubitril/valsartan ACEi, angiotensin converting enzyme inhibitor; ADHF, acute decompensated
heart failure; ARB, angiotensin receptor blocker; b.i.d, twice daily; HF, heart
failure; OMT, optimal medical treatment for HF; sac/val, sacubitril/valsartan
Pascual-Figal, et al. ESC Heart Failure (Epub ahead of print)

12. TRANSITION study design
ACEi, angiotensin converting enzyme inhibitor; ADHF, acute decompensated heart
failure; ARB, angiotensin receptor blocker; b.i.d, twice daily; HF, heart failure; OMT,
optimal medical treatment for HF; sac/val, sacubitril/valsartan
Treatment epoch
10 weeks’ duration starting at randomization
1-3 days’
screening epoch
16 weeks’
follow-up epoch
Open-label
Sac/val 50 mg  100 mg b.i.d.  200 mg b.i.d.
or
Sac/val  100 mg  200 mg b.i.d.
as per label and at investigator discretion
Open-label
Sac/val 50 mg  100 mg b.i.d.  200 mg b.i.d.
or
Sac/val  100 mg  200 mg b.i.d.
as per label and at investigator discretion
OMT continued throughout the study (excluding ACEi/ARB)
Any OMT as
per treating
physician OMT continued throughout the study (excluding ACEi/ARB)
Patient stabilized
3 strata
OMT but
ACEi/ARB
naïve pts
PRE-discharge initiation
POST-discharge initiation
36 h ACEi
washout
Hospital
admission
for ADHF
ACEi + OMT
ARB + OMT
RandomizationtoPRE-orPOST-discharge
36 h ACEi
washout
Open-labelsac/val
attolerateddose
Discharge
Down-titration or temporary discontinuation of sac/val is allowed in all groups at any time
max. 2 weeks
Any OMT as per
treating
physician
Pascual-Figal, et al. ESC Heart Failure (Epub ahead of print)

13. Clinicaltrials.gov identifier:
NCT02661217. ESC Congress,
Munich, 2018. P6531

14. Characteristics
Pre-discharge
N= 497
Post-
discharge
N= 496
Total
N= 993
Prior heart failure history – n (%)
No 148 (29.8) 138 (27.8) 286 (28.8)
Yes 349 (70.2) 358 (72.2) 707 (71.2)
First onset (de novo) HF n (%) 148 (29.8) 138 (27.8) 286 (28.8)
Prior hospitalisation for HF n (%) 237 (47.7) 248 (50.0) 485 (48.8)
Date of HF diagnosis – n (%)
>0 to 3 months 23 (6.6) 21 (5.9) 44 (6.2)
>3 to 6 months 16 (4.6) 19 (5.3) 35 (5.0)
>6 to 12 months 35 (10.0) 32 (8.9) 67 (9.5)
>1 to 2 years 37 (10.6) 40 (11.2) 77 (10.9)
>2 to 5 years 94 (26.9) 92 (25.7) 186 (26.3)
>5 years 144 (41.3) 152 (42.5) 296 (41.9)
Clinicaltrials.gov identifier: NCT02661217. ESC Congress, Munich, 2018. P886
Data on-file

15. TRANSITION patients’ strata
Stratification based on use of RAAS medications
prior to hospitalization
ACEI/ARB -naïve patients
defined as either:
• without any previous treatment
with ACEI or ARBs, or
• without ACEI/ARB therapy for
at least 4 weeks before hospital
admission due to ADHF
as reported in IVRS
Clinicaltrials.gov identifier: NCT02661217. ESC Congress, Munich, 2018. P886

16. Primary and secondary endpoints
45
62,5
86,4
4,5
50,4
68
[VALOR]
3,5
0
10
20
30
40
50
60
70
80
90
100
Proportionofpatients(%)
Primary endpoint
On target dose 200 mg bid
of sac/val at Week 10
Achieved and maintained
100 mg and/or 200 mg bid
of sac/val or at least 2
weeks leading to Week 10
Achieved and maintained
any dose of sac/val for at
least 2 weeks leading to
Week 10
Permanently
discontinued sac/val
due to AE
RRR 0.89 (0.78, 1.02)
P= 0.092
RRR 0.92 (0.84, 1.01)
P= 0.071
RRR 0.97 (0.93, 1.02)
P= 0.262
RRR 1.29 (0.69, 2.39)
P= 0.424
Pre-discharge
initiation (N= 493)
Post-discharge
initiation (N= 490)
AE, adverse events; bid, twice daily; sac/val, sacubitril/valsartan;
RRR, relative risk ratio
* Safetyl analysis set
Clinicaltrials.gov identifier: NCT02661217. ESC Congress, Munich, 2018. P886

17. AEs and treatment interruptions
AE, adverse event; SAE, serious adverse event * Fischer’s Exact Test, Full analysis set
Pre-discharge
N= 497
n (%)
Post-discharge
N= 496
n (%)
P value*
Patients with 1 AE, n (%) 338 (68.0) 323 (65.1) 0.335
Patients with 1 SAE, n (%) 94 (18.9) 88 (17.7) 0.682
Deaths, n (%) 13 (2.6) 10 (2.0) 0.674
Temporary treatment interruption, n (%)
Due to AEs 70 (14.1) 55 (11.1) 0.180
Due to SAEs 21 (4.2) 8 (3.6) 0.744
Due to non-SAEs 54 (10.9) 42 (8.5) 0.237
Permanent treatment discontinuation, n (%)
Due to AEs 22 (4.4) 20 (4.0) 0.875
Due to SAEs 15 (3.0) 13 (2.6) 0.848
Due to non-SAEs 8 (1.6) 7 (1.4) 1.000
Clinicaltrials.gov identifier: NCT02661217. ESC Congress, Munich, 2018. P886

18. Most common AEs† during 10-week treatment
epoch regardless of study drug relationship
AE, adverse event * Fischer’s Exact Test, Full analysis set
Pre-discharge
N= 497
n (%)
Post-discharge
N= 496
n (%)
P value*
Hyperkalemia 55 (11.1) 56 (11.3) 0.920
Hypotension 61 (12.3) 45 (9.1) 0.123
Cardiac failure 34 (6.8) 42 (8.5) 0.343
Dizziness 28 (5.6) 21 (4.2) 0.380
Peripheral edema 17 (3.4) 24 (4.8) 0.270
Renal impairment 25 (5.0) 15 (3.0) 0.146
Diarrhea 12 (2.4) 23 (4.6) 0.060
Urinary tract infection 20 (4.0) 15 (3.0) 0.492
† ≥4% of patients in any group
Clinicaltrials.gov identifier: NCT02661217. ESC Congress, Munich, 2018. P886

19. Most common Serious Adverse Events*
COPD, chronic obstructive pulmonary disease;
SAE, serious adverse event
** Fischer’s Exact Test, Full analysis set
Pre-discharge
N= 497
n (%)
Post-discharge
N= 496
n (%)
P value**
No. of patients with at least one SAE 94 (18.9) 88 (17.7) 0.682
Hyperkalemia 3 (0.6) 2 (0.4) 1.000
Hypotension 4 (0.8) 2 (0.4) 0.687
Atrial fibrillation 3 (0.6) 4 (0.8) 0.726
Cardiac failure (acute/chronic) 35 (7.0) 38 (7.7) 0.717
Ventricular tachycardia 3 (0.6) 0 (0.0) 0.249
Non-cardiac chest pain 0 (0.0) 3 (0.6) 0.124
Pneumonia 4 (0.8) 3 (0.6) 1.000
Respiratory tract infection 0 (0.0) 3 (0.6) 0.124
Acute kidney injury 6 (1.2) 7 (1.4) 0.789
Renal failure 3 (0.6) 1 (0.2) 0.624
Pulmonary edema 3 (0.6) 2 (0.4) 1.000
COPD 0 (0.0) 4 (0.8) 0.062
* ≥0.5% of patients in any group
Clinicaltrials.gov identifier: NCT02661217. ESC Congress, Munich, 2018. P886

20. Predictors for successful sacubitril/valsartan
dose up-titration to 200 mg bid
AE, adverse event; CI, confidence interval; eGFR,
estimated glomerular filtration rate; HF, heart
failure; sac/val, sacubitril/valsartan; SBP, systolic
blood pressure
For the results shown above, only significant
(p <0.05) predictors and treatment group
(significant or not) are kept in the model
Age (<65 years vs. ≥65 years)
eGFR at baseline (≥60 mL/min·1.73 m2
vs. <60 mL/min·1.73 m2)
SBP at baseline ≥120 mmHg vs.
≥100-120 mmHg
Prior HF history (No vs. Yes)
Medical history of hypertension
(Yes vs. No)
Atrial fibrillation at baseline (No
vs. Yes)
Starting dose of sac/val (100 mg
vs. 50 mg)
Treatment (post-discharge vs.
pre-discharge)
1.42
1.52
1.48
1.59
1.85
1.77
2.41
1.20
(1.05, 1.93)
(1.13, 2.03)
(1.11, 1.97)
(1.15, 2.19)
(1.31, 2.63)
(1.33, 2.35)
(1.57, 3.68)
(0.91, 1.58)
0.023
0.005
0.008
0.005
0.001
<0.001
<0.001
0.196
Predictor Odds ratio 95% CI P value
1 2 3 4
Clinicaltrials.gov identifier: NCT02661217. ESC Congress, Munich, 2018. P886

21. TRANSITION
Sac-Val (both initiation
and titration) is feasible
and safe in the
Transition period of a
patient hospitalized due
to HF
Pascual-Figal DA. Eur J Heart Fail. 2017; 19(8): 1.011-1.013
Greene SJ, Mentz RJ, Felker GM. JAMA Cardiol. 2018; 3: 252

22. Koehler F. Clinicaltrials.gov identifier: NCT01878630. ESC Congress, Munich, 2018

23. Koehler F. Clinicaltrials.gov identifier: NCT01878630. ESC Congress, Munich, 2018

24. Características basales de la población
Koehler F. Clinicaltrials.gov identifier: NCT01878630. ESC Congress, Munich, 2018

25. % day lost due to unplanned CV hospitalisations
and all-cause death
Koehler F. Clinicaltrials.gov identifier: NCT01878630. ESC Congress, Munich, 2018

26. Koehler F. Clinicaltrials.gov identifier: NCT01878630. ESC Congress, Munich, 2018

27. % days lost due to unplanned HF hospitalisations
Koehler F. Clinicaltrials.gov identifier: NCT01878630. ESC Congress, Munich, 2018

28. Koehler F. Clinicaltrials.gov identifier: NCT01878630. ESC Congress, Munich, 2018

29. Clinicaltrials.gov identifier: NCT02992288. ESC Congress, Munich, 2018

30. Clinicaltrials.gov identifier: NCT02992288. ESC Congress, Munich, 2018

31. Clinicaltrials.gov identifier: NCT02992288. ESC Congress, Munich, 2018

32. No efecto comparado
con placebo
Clinicaltrials.gov identifier: NCT02992288. ESC Congress, Munich, 2018

33. Microvascular dysfunction in heart failure with preserved
ejection fraction (HFpEF) evidence from PROMIS-HFpEF
Carolyn SP, et al. ESC Congress, Munich, 2018

34. Carolyn SP, et al. ESC Congress, Munich, 2018

35. InterAtrial Shunt Device (IASD®)
Feldman T, Shah SJ, et al. Circ Heart Fail. 2016 Jul; 9(7) NCT02600234

36. Feldman T. ESC Congress, Munich, 2018

37. Feldman T. ESC Congress, Munich, 2018

38. Shunt Patency
Feldman T. ESC Congress, Munich, 2018

39. Change in NYHA Functional Class:
InterAtrial Shunt Device vs. Sham Control
Feldman T, MD. ESC Congress, Munich, 2018

40. Feldman T. ESC Congress, Munich, 2018

41. Decreased AF burden with dynamic optimization of CRT
pacing using the AdaptivCRT algorithm in Heart Failure
patients: Analysis of real-world patient data
Figure: Highlight ESC Munich. Aug 29, 2018
Singh J, et al. Eur Heart J. 2018; 39: 482. P2491

42. Singh J, et al. Eur Heart J. 2018; 39: 482. P2491

43. Singh J, et al. Eur Heart J. 2018; 39: 482. P2491

44. Impact of mineralocorticoid receptor antagonists on sudden cardiac
death in patients with heart failure and left ventricular systolic
dysfunction: a meta-analysis of three randomized controlled trials.
X. Rosselló (Palma de Mallorca, ES)
• Se presenta un metanálisis de 3 estudios sobre el uso de antagonistas de los
receptores de mineralocorticoide (MAR) en pacientes con ICFEr en la
incidencia de muerte súbita (MS) con 11.032 pacientes vs. placebo
• Estudios RALES, EPHESUS y EMPHASIS-HF
• Conclusiones:
– Los MAR reducen un 23% el riesgo de MS en pacientes con ICFEr
(objetivo 1)
– El uso de MAR debería tenerse en cuenta como terapia de primera línea,
así como las otras con clara evidencia (BB IECAS)
Rosselló X. Eur Heart J. 2018; 39: 17

45. • Conclusiones:
– La terapia guiada de concentración sérica de digoxina se asoció con un
aumento de la mortalidad en pacientes con ICFEr con óptimo tratamiento
médico
– Solo en niveles séricos <0,9 ng/mL no se objetivó un aumento de
mortalidad
– Se refuerza la opinión de expertos que digoxina debería ser usada
cuidadosamente en pacientes seleccionados con niveles controlados
The impact of serum concentration guided digoxin therapy on
mortality: a long-term follow-up, propensity-matched cohort
study. B. Muk (Budapest, HU)
Muk B, et al. European Heart Journal, Volume 39,
Issue suppl_1, 1 August 2018, ehy564.205,
https://doi.org/10.1093/eurheartj/ehy564.205"

46. Characteristics of heart failure patients treated
with Sacubitril-Valsartan in Europe. Results from ARIADNE
Zeymer U, et al. Eur Heart J. 2018; 39: 174

47. Zeymer U, et al. Eur Heart J. 2018; 39: 174

48. Beware of making dose comparisons for efficacy
in post-hoc analyses of achieved dose in up-titrating studies:
lessons from the EMPHASIS trial
Ferreira JP, et al. Eur Heart J. 2018; 174(39): 910

49. Tolerability and safety of sacubitril/valsartan
in high-risk subgroups
Neiva JN, et al. Eur Heart J. 2018; 174-175(39): 911

50. Treatment with insulin is associated with worse outcome
in patients with chronic heart failure and diabetes
Cosmi D, et al. Eur Heart J. 2018; 39: 680

51. Cosmi D, et al. Eur Heart J. 2018; 39: 680

52. Cosmi D, et al. Eur Heart J. 2018; 39: 680

53. – Independiente de la adherencia del médico a las guías clínicas, la adherencia del paciente jugó
un rol clave en pacientes con IC, en cuanto a la mortalidad y las rehospitalizaciones por IC
Physician and patient adherence to guidelines is associated with better prognosis
in patients with heart failure: insights from the Optimize Heart Failure Care
Program. Y. M. Lopatin (Volgograd, RU)
Lopatin YM, et al. Eur Heart J. 2018; 39: 19

54. The role of statins in patients with heart failure with
preserved, mid-range, and reduced ejection fraction.
A meta-analysis and systematic review
Science and Fiction in heart failure

55. Fourth Universal Definition of Myocardial Infarction (2018). J Am Coll Cardiol. 2018; 25 [Epub ahead of print]

56.  IC asociada a envejecimiento y comorbilidad, precisa esfuerzo
organizativo
 Sacubitrilo-valsartán presenta buena tolerancia y es factible en el
periodo vulnerable tras una hospitalización por IC
 Datos favorables de telemedicina posthospitalización, 24 h/7días y sin
depresión.
 TRC adaptada puede prevenir FA
 ICFE preservada: disfunción microvascular y shunt interatrial
 Fármacos con evidencia deben ser usados y optimizados en la vida
real de forma adecuada
Mensajes finales