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New molecules · • Levosimendan • Oral ... • ADHF • Post MI • NYHA IV • Pediatric study...
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New molecules Alain COHEN SOLAL Cardiologie, UMR-S 942, Université Paris Diderot, Paris Cité Sorbonne Hôpital Lariboisière, Paris
Transcript of New molecules · • Levosimendan • Oral ... • ADHF • Post MI • NYHA IV • Pediatric study...
New molecules
Alain COHEN SOLAL Cardiologie, UMR-S 942,
Université Paris Diderot, Paris Cité Sorbonne Hôpital Lariboisière, Paris
Therapeutic algorithm for a patient with symptomatic HF with reduced ejection fraction.
Available online on Eur J Heart Fail
Therapeutic algorithm for a patient with symptomatic HF with reduced ejection fraction. (cont..)
New molecules • IV • Serelaxine • Ularitide • Levosimendan
• Oral • Ivabradine • LCZ696 • Vericiguat • Omecamtiv Mecarbil
0 6 12 18 24 30 Mois
40
30
20
10
Ivabradine
Placebo RRR= 18% p<0,0001
Events HR 95% CI p value All cause mortality 0,90 0,80;1,02 P=0,092
CV mortality 0,91 0,80;1,03 p=0,128
HF mortality 0,74 0,58;0,94 p=0,014
HF hospitalisation 0,74 0,66;0,83 p<0,0001
All cause hospitalisation 0,89 0,82;0,96 p=0,003 CV cause hospitalisation 0,85 0,78;0,92 p=0,0002
NNT: 26 patients during 1 year
SHIFT : benefit of ivabradine in HF with HR ≥ 70bpm
Swedberg K, Komajda M et al. Lancet 2010; 376: 875–85
CV mortality ou HF hospitalisation
Bas
elin
e
Bas
elin
e
M00
8
M00
8
∆ VTSVGi Procoralan vs Placebo = -5,8; p <0,001
Evolution à 8 mois du critère primaire Volume TéléSystolique du VG indexé
∆ - 7,0 ± 16,3 ∆ - 0,9 ± 17,1 In
clus
ion
Incl
usio
n
M08
M08
65,2
58,2 63,6 62,8
J.C. Tardif et al., doi:10.1093/eurheartj/ehr311
Echo
Ivabradine en association précoce aux bêtabloquants
- 9 -
2 semaines
+ Procoralan 7,5mg 2x/j
1 mois 1/2 Inclusion
Insuffisants cardiaques stables
NYHA II-III, ATCD IDM,
FEVG < 40%, FC≥ 70 (n=69)
-2 mois Pas de bêtabloquant
1 mois
Carvedilol 3,125mg 2x/j
Carvedilol 6,5mg 2x/j
Carvedilol 12,5mg 2x/j
+ Procoralan 5mg 2x/j
+ Procoralan 5mg 2x/j
+ Procoralan 7,5mg 2x/j
Carvedilol 25 mg 2x/j
+ Placebo + Placebo + Placebo + Placebo
Carvedilol 3,125mg 2x/j
Carvedilol 6,5mg 2x/j
Carvedilol 12,5mg 2x/j
Carvedilol 25 mg 2x/j
Doublement des doses de Carvedilol toutes les 2 semaines
Bagriy AE. et al. Adv Ther 2015
69 insuffisants cardiaques (NYHA II ou III), avec FE < 40 %, en rythme sinusal, FC de repos ≥ 70 Bpm, ATCD d’infarctus du myocarde, n’ayant pas reçu de bétabloquants
depuis au moins 2 mois et n’ayant jamais reçu d’ivabradine.
Thérapie standard : IEC/ARAII,
diurétiques, anti-aldostérone, statines
Visites à 2, 4, 6 semaines, 3 et 5 mois Evaluation de la FC (ECG), PA, EI, dosages
69 insuffisants cardiaques (NYHA II ou III), avec DVG (FE < 40 %), en rythme sinusal, FC de repos ≥ 70 Bpm, ATDC d’infarctus du myocarde, n’ayant pas reçu de bétabloquants depuis au moins 2 mois et n’ayant jamais reçu d’ivabradine.
* P< 0.05 versus patients sous carvédilol seul
Ivabradine et titration des bêtabloquants
Bagriy AE. et al. Adv Ther 2015
Action hémodynamique de l’ivabradine IV dans l’IC
De Ferrari GM Eur J Heart Failure 2008
10 patients hospitalisés avec insuffisance cardiaque congestive sévère (NYHA III), DVG avancée (FEVG moyenne 21%) et FC ≥ 80 bpm traités par bétabloquants
Action hémodynamiques de l’ivabradine IV dans l’IC
De Ferrari GM Eur J Heart Failure 2008
10 patients hospitalisés avec insuffisance cardiaque congestive sévère (NYHA III), DVG avancée (FEVG moyenne 21%) et FC ≥ 80 bpm traités par bétabloquants
McMurray et al. N Engl J Med 2014;371:993-1004
Primary & secondary outcomes 8399 patients
-20% -20%
-21% -16%
McMurray et al. N Engl J Med 2014;371:993-1004
Primary & secondary outcomes 8399 patients
-20% -20%
-21% -16%
30-day HF hospitalizations after randomisation
HR 0.60 (95% CI: 0.38–0.94) p=0.027
Days after randomization Number of patients at risk LCZ696 4,187 4,174 4,153 4,140 Enalapril 4,212 4,192 4,166 4,143
K
apla
n-M
eier
est
imat
e of
cu
mul
ativ
e ra
te
1.5
1.0
0.5
0 0 10 20 30
Enalapril (N=4,212) LCZ696 (N=4,187)
Packer et al. Circulation 2014; epub ahead of print: DOI: 10.1161/CIRCULATIONAHA.114.013748
Shown is the Kaplan-Meier estimate of the cumulative probability of a first hospitalization for heart failure during the first 30 days after randomization. The analysis at 30 days was prespecified and also represented the earliest time point at which the difference between the LCZ696 and enalapril groups was statistically significant.
Heart failure hospitalization
Number and rate of 30-day and 60-day re-hospitalizations
104 (9.7%)
67
175 (13.4%)
119
0
50
100
150
200
Total number of 30-dayreadmissions for HF
Patients with 30-dayreadmission for HF
30- day readmissions for HF
Enalapril LCZ696
60- day readmissions for any cause
294 (27.8%)
177
391 (30.5%)
251
0
50
100
150
200
250
300
350
400
450
Total number of 60-dayreadmissions for any cause
Patients with 60-day readmissionfor any cause
Adjusted OR: 0.62 (0.45–0.87); p=0.006 Adjusted OR: 0.77 (0.60–0.99);
p=0.045
Adjusted OR: 0.56 (0.41–0.76); p<0.001
Adjusted OR: 0.70 (0.57–0.85); p<0.001
Num
ber (
n)
Num
ber (
n)
OR=odds ratio; HF=heart failure
Desai JACC V O L . 6 8 , NO . 3 , 2 0 1 6
Sudden cardiac deaths
Hazard ratio = 0.80 (95% CI: 0.68–0.94) p=0.008
Enalapril LCZ696
0 180 360 540 720 900 1,080 1,260 0
0.02
0.04
0.06
0.08
0.10
Days since randomization No. at risk LCZ696 4,187 3,891 2,478 1,005 Enalapril 4,212 3,860 2,410 994
Cum
ulat
ive
prob
abili
ty o
f eve
nt
*Resuscitated sudden deaths were defined as successful resuscitation following cardiac arrest
CI=confidence interval; HR=hazard ratio Desai et al. Eur Heart J 2015;36:1990-1997
The LCZ696 treatment effect for sudden cardiac death was not influenced by the presence of defibrillator devices
Death due to worsening of heart failure
Enalapril LCZ696
Hazard ratio = 0.79 (95% CI: 0.64–0.98) p=0.034
0 180 360 540 720 900 1,080 1,260 0
0.02
0.04
0.06
0.08
0.10
Cum
ulat
ive
prob
abili
ty o
f eve
nt
Days since randomization No. at risk LCZ696 4,187 3,891 2,478 1,005 Enalapril 4,212 3,860 2,410 994
CI=confidence interval Desai et al. Eur Heart J 2015;36:1990-1997
Of those who died due to heart failure, 33.2% experienced a hospitalization for heart failure prior to death
Ongoing trials in HF
• ADHF • Post MI • NYHA IV • Pediatric study • Cardio Oncology • …
Ongoing Morbimortaliy Trial
Effects of IV serelaxin on PCWP
Hemodynamic parameter Serelaxin
(n=32) Placebo (n=31)
Treatment difference [95% confidence interval] p-value
Time-weighted average: 0–20 h –4.46 (0.59) –2.04 (0.60) –2.42 [–4.08, –0.76] 0.0042
Time-weighted average: 20–24 h –4.41 (0.83) –3.11 (0.85) –1.30 [–3.63, 1.03] 0.27
Data represented as mean ± SE
Data represented in mmHg as least squares mean (SE) change from baseline Time-weighted average is based on area under the effect curve for the corresponding time interval PCWP=pulmonary capillary wedge pressure; SE=standard error Ponikowski P, et al. Late-breaking clinical trial presented at ESC-HF 2013
28
27
26
25
24
23
22
21
20
Pulm
onar
y ca
pilla
ry w
edge
pr
essu
re (m
mHg
)
0 0.5 2 4 6 8 20 21 22 24
Hours post-dose
Serelaxin Placebo
Treatment group
D180
Treatment
Likert
Timeline:
VAS AUC
D1 D5 D14/Index
Days Alive Out of Hospital
CV death+ HF/RF Re-hospitalization
LoS (index/ICU)
WHF
D2 D60
In-hospital benefits Out-patient benefits
D0
CV death
6, 12, 24 h
Serelaxin
0-100 mm; 0, 6, 12, 24h, D2-D5 Prim
ary
EP
Seco
ndar
y EP
p<0.025 for either 1° Dyspnea EP or p<0.05 for both 1° Dyspnea EPs
Biomarkers
RELAX-AHF
Placebo
Cumulative proportion of worsening heart failure to Day 5 (%)
Worsening of Heart Failure
0
2
4
6
8
10
12
14
16
18
6 hr 12 hr Day 1 Day 2 Day 3 Day 4 Day 5
Placebo (N=573)
Serelaxin (N=570)
Kaplan-Meier estimate D14 for time to WHF (%)
11 3 16 4 31 10 44 17 57 25 64 69 37 36 0
2
4
6
8
10
12
14
16
18
Day 5 Day 14
573 570
**HR 0.7 (0.51, 0.96); p=0.024
n= 573 570
*p<0.001 through Day 5
Worsening Heart Failure (WHF) was defined as worsening signs and/or symptoms of HF that required an intensification of IV therapy for heart failure or mechanical ventilatory or circulatory support. *p value by Wilcoxon test **p value by log rank test for Serelaxin vs. Placebo; HR estimate by Cox model, HR<1.0 favors Serelaxin
CV Death through Day 180
0 0
14
12
10
8
6
4
2
14 30 60 90 120 150 180
HR 0.63 (0.41, 0.96); p=0.028 55 (9.5%)
35 (6.0%)
Placebo (N=580)
Serelaxin (N=581)
Number of Events, n (%)*
NNT = 29
Days 580 567 559 547 535 523 514 444 Placebo 581 573 563 555 546 542 536 463 Serelaxin
K-M estimate for CV Death ITT (%)
Ongoinng Trial
• RELAX-AHF 2 • Results 2017
Conclusions
• New drugs on the blocks • But advanced HF is difficult to treat • Importance of therapy early in the course of
HF
