Immediate care of newborn, midwifery and obstetrical nursing
Serelaxin.
1. Acute heart failure:
Novel therapies on the horizon
Serelaxin
John R. Teerlink, MD
FACC, FAHA, FESC, FRCP(UK)
Professor of Medicine,
University of California San Francisco
Director, Heart Failure and Director, Echocardiography
San Francisco VA Medical Center
23.May, 2015
Sevilla, Spain
2. • Financial Disclosure
– J.R. Teerlink has received research grants
and/or consulting fees from Amgen,
Cytokinetics, Janssen, Medtronic, Novartis, St.
Jude, Takeda, and Trevena.
• Unlabeled/unapproved uses disclosure
– I will be discussing investigational therapies
that are not approved by the FDA or EMA.
UCSF
Presenter Disclosure Information:
Heart Failure 2015
3. Acute heart failure:
Novel therapies on the horizon
Lippicky RJ and Packer M. J Am Coll Cardiol 1993;22(4 Suppl A):179A-184A.
“To be of clinical value in the
treatment of heart failure, a drug must
permit patients either to feel better or
to live longer, or both.”
4. • Onset of hemodynamic changes coincident with relaxin-2 elevation during 1st
trimester of pregnancy; similar but smaller changes observed during the luteal phase
of menstrual cycle
• Systemic and renal vasodilation occur in parallel, a unique facet of pregnancy
• Systemic and renal hemodynamics recapitulated in rodent models using serelaxin
and similar effects observed in human studies
Maternal Hemodynamic Adaptations to
Pregnancy
PARAMETER PREGNANCY
Systemic vascular
resistance (dyn.s.cm2)
30%
Cardiac output (L/min) 20%
Global arterial compliance
(mL/mm Hg)
30%
Renal vascular resistance
(dyn.s.cm2)
20%
Renal blood flow
(mL/min/1.73m2)
50-85%
Creatinine clearance
(mL/min/1.73m2)
40-65%
Baylis, C. Am J Kid Dis 1999; Schrier, RW, et al. Am J Kid Dis 1987; Jeyabalan, A, et al. Adv Exp Med Biol 2007
5. Pre-RELAX-AHF: Main Conclusions
• 234 patient, dose finding Phase II study
• With optimal dose across multiple clinical outcome
domains was 30mcg/kg/d serelaxin had trends to:
Teerlink JR, et al. Lancet 2009;373:1429–1432.
- Improved dyspnea relief/
clinical course
- Decreased congestion
- Reduced diuretic use
- Less worsening heart
failure
- Shorter length of stay
- Reduced days alive out
of hospital
- ??? Improved
cardiovascular and all-
cause survival
• No significant adverse events
• No hypotension SAEs; Hypotension AEs similar to
placebo
6. Post-discharge evaluation period
Placebo (n=580)
Serelaxin 30 µg/kg/d (n=581)
0 6 12 24 48 h 5 d 14 d 60 d 180 d
48 h study drug
infusion period
Screening
Double-blind, randomized treatment and follow up period
Presentation <16 h
1,161 patients
hospitalized for AHF
RELAX-AHF: Study design
Teerlink JR, et al. Lancet 2013; 381:29-39.
Standard HF therapy
During study investigators free to use any concomitant
medications incl. nitrates according to clinical judgment
Entry Criteria:
• Dyspnea, Congestion
on CXR, Elevated BNP/
nt-ProBNP
• SBP >125 mmHg
• eGFR 30-75 ml/min
1.73m2
• ≥40 mg IV furosemide
Excluded:
• Acute Coronary
Syndrome
• High dose nitrates
7. Clinical events supersede symptoms at the time of their occurrenceClinical events supersede symptoms at the time of their occurrence
Visual Analog Scale Area Under the Curve:
Dyspnea Clinical Composite
DeathDeath
In-hospitalIn-hospital
worseningworsening heartheart
failurefailure
Change inChange in
dyspnea scoredyspnea score
8. Visual Analog Scale
Area Under Curve
Visual Analog Scale AUC
With Worst Score Assignment
Moderate or marked
worsening of symptoms at
any planned assessment
Unresponsive or worsening
heart failure requiring IV or
mechanical interventions
Worsening heart failure
requiring IV or mechanical
interventions
Death Death
Visual Analog Scale
Area Under Curve
No dyspnea
Severe dyspnea
Numerical scores
over time
Worst score
9. 543210
0
5
10
15
20
25
30
35
AUC with placebo, 2308 ± 3082
AUC with serelaxin, 2756 ± 2588
p=0.0075
Changefrombaseline
(mm)
19.4% increase in AUC with
serelaxin
from baseline through day 5
(Mean difference of 448 mm-hr)
Days
6
Serelaxin
Placebo
12 hrs
Teerlink JR, et al. Lancet 2013; 381:29-39.
1° Endpoint:
Visual Analog Scale Area Under the Curve Composite
10. **HR 0.7 (0.51, 0.96); p=0.024
Cumulative proportion of worsening heart failure
to Day 5 (%)
Worsening of Heart Failure
6 hr 12 hr Day 1 Day 2 Day 3 Day 4 Day 5
0
2
4
6
8
10
12
14
16
18
Placebo (N=573)
Serelaxin (N=570)
Kaplan-Meier estimate D14
for time to WHF (%)
11 3 16 4 31 10 44 17 5725 64 69 3736
Day 5 Day 14
0
2
4
6
8
10
12
14
16
18
573 570
(Numbers of subjects with WHF shown for each time point)
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.
n= 573 570
*p<0.001 through Day 5
*p value by Wilcoxon test; **p value by log rank test for Serelaxin vs. Placebo; HR estimate by Cox model
10
Teerlink JR, et al. Lancet 2013; 381:29-39.
11. Placebo
(N=580)
Serelaxin
(N=581)
Patients with WHF event included in the analysis
of the 5-day primary endpoint
69 37
Patients who died or who experienced WHF
leading to rehospitalization within 5 days
5 4
Patients with WHF within 5 days treated with
IV positive inotropic drug or mechanical intervention
17 6
Patients with WHF within 5 days treated with
new IV nitrates or IV nitroprusside
13 7
Patients with WHF within 5 days treated with
reinitiation or doubling of daily dose of IV diuretic
14 7
Total 49 24
Worsening Heart Failure Events
With More Intensive Rescue Intervention
P=0.003Teerlink JR, et al. ESC 2014 Clinical Trial Update
12. Primary Endpoint Sensitivity Analyses
Based on Clinically Ranked Outcomes
PP valuevalue
Analysis of clinically ranked outcomes
All worsening heart failure events assigned
same rank
0.0190
Earlier worsening heart failure events assigned
worse rank than later events*
0.0110
Recurrent worsening events assigned worse rank
than single events
0.0150
Aggressive interventions ranked worse than
IV vasodilators, ranked worse than IV diuretics
0.0183
Prespecified primary efficacy analysis 0.0075
Observed VAS scores and log rank test used; Modified from Finkelstein & Schoenfeld (1999) and Felker (2010)
Teerlink JR, et al. ESC 2014 Clinical Trial Update
13. Fewer Serelaxin Treated Patients Required IV
Diuretics, Vasodilators, Inotropes and Mechanical Support
0
50
100
150
200
250
N=572 N=570
IVdiureticsuse(cumulative
totaldosefromday1-5[mg])
*p=0.006
Placebo Serelaxin
24%
difference
Less use of IV diuretics in
serelaxin group
0
10
20
30
40
50
60
70
80
90
100
N=580 N=581
PatientstreatedwithIVvasodilators,
InotropesorMechanicalSupport(n)
*p=0.017
Placebo Serelaxin
30%
difference
16.4%
11.5%
Less use of IV Vasodilators,
Inotropes and Mechanical
Support in serelaxin group
14. P value by Wilcoxon rank sum test (death assigned longest length of stay plus 1 day)
Length of Stay in Hospital and ICU/CCU
Index Hospitalization ICU/CCU
Placebo Serelaxin
0
1
2
3
4
5
Placebo Serelaxin
0
2
4
6
8
10
12 P=0.039
n=578 n=574
P=0.029
n=580 n=581
0.9 days
less than
placebo
0.3 days
less than
placebo
LengthofStay(Days)
ICU/CCUStay(Days)
Teerlink JR, et al. Lancet 2013; 381:29-39.
15. All-cause mortality in the RELAX-AHF
program
1.00
0.98
0.96
0.94
0.92
0.90
0.88
0.86
0.84
0.82
Survivalprobability
0 20 40 60 80 100 120 140 160 180
Study Day
Pre-RELAX-AHF:
Placebo
Pre-RELAX-AHF:
Serelaxin
RELAX-AHF: Placebo
RELAX-AHF: Serelaxin
Combined: Placebo
Combined: Serelaxin
HR (95%CI), P value
• Pre-RELAX: 0.53 (0.22,1.30), p =
0.16
• RELAX-AHF: 0.63 (CI 0.43, 0.93);
p=0.020
• Combined: 0.62 (0.43-0.88),
p=0.0076
Metra M, et al. J Am Coll Cardiol 2013;61:196-206.
16. Dyspnea Relief (VAS AUC Day 5) CV Death Through 180 Days
Metra M, et al. Eur Heart J 34:3128-36.
17. Cardiovascular mortality in Patients
with HFpEF in RELAX-AHF
Filippatos G, et al. Eur Heart J 2014;35:1041-1050.
18. Hemodynamic Effects of Serelaxin
in Patients with Acute Heart Failure
18
v Study objective: To evaluate the hemodynamic effects of serelaxin in 71 patients
with AHF at a dose rate of 30 µg/kg/day
Swan-Ganz catheter inserted ≥ 1 h prior to randomization
4h post-
infusion
30 d
20 h study drug infusion
Placebo
Serelaxin 30 µg/kg/d
Double-blind, randomized
treatment period
Serelaxin 100 µg/kg/d (n=37)
Serelaxin 250 µg/kg/d (n=49)
Patients hospitalized with AHF,
mean PCWP ≥18 mmHg,
SBP ≥115 mmHg, and
estimated glomerular filtration
rate ≥30 ml/min/1.73m2
Screening
≤48 h
Presentation
Randomized 1:1
0 h 8 h 20 h 24 h
Safety evaluation
Washout
Washout
Ponikowski P, et al. Eur Heart J 2014;35:431-441.
19. Hemodynamic Effects of Serelaxin
in Patients with Acute Heart Failure
Ponikowski P, et al. Eur Heart J 2014;35:431-441.
*
*
*
*
* *
* * *
*
20. Renal Hemodynamic Effects of Serelaxin
in Patients with Chronic Heart Failure
*Measured by plasma clearance of PAH and IOTH. CHF, chronic heart failure; GFR, glomerular filtration rate; IOTH, iothalamate; i.v.,
intravenous; PAH, para-amino-hippuric acid; RPF, renal plasma flow
v Study objectives: To assess the renal hemodynamic effects of 24 h i.v.
infusion of serelaxin, as determined by RPF and GFR in CHF patients*
8 10 11 13 15 17 19 23 3 7 11 13 15
Day -21 to -1 Day 1 Day 2
11:30
–3 –1 0 2 4 6 8 12 16 20 22 23 24 26 2824.5
Time of day:
Wash-out
Wash-out
Furosemide infusion
IOTH/PAH
Urine
collection
Screening
Randomization
Placebo
Serelaxin 30 µg/kg/day i.v. infusion
0:10
0:30
20
Chronic HF
NHHA II-III
LVEF ≤45%
BNP ≥100 pg/mL
or NT-proBNP
≥400 pg/mL
Worsening sx
within 3 mo
SBP≥110 mmHg
Voors AA, et al. Circ Heart Fail 2014;7:994-1002.
21. Renal Hemodynamic Effects of Serelaxin
in Patients with Chronic Heart Failure
21
Time-weighted average
change from baseline
Serelaxin
(n = 28)
Placebo
(n = 37)
Treatment
difference†
(95% CI)
p-value
0–24 h 1.31 (1.05) 1.13 (1.04) 1.16 (1.05, 1.28) 0.0042
8–24 h 1.29 (1.05) 1.14 (1.05) 1.13 (1.01, 1.27) 0.0386
24–28 h 1.35 (1.05) 1.16 (1.05) 1.16 (1.03, 1.30) 0.0115
CI, confidence interval; SE, standard error
Data presented as least squares geometric mean ratio to baseline (standard error).†Ratio of least squares geometric mean ratios
*p≤0.05 vs. placebo
282422
600
500
400
300
700
0
200
Serelaxin
Placebo
2 4 6 8 20 26
Geomean(±SE)renalplasma
flow(mL/min)
Hours post-dose
*
* *
* * *
Voors AA, et al. Circ Heart Fail 2014;7:994-1002.
23. Risk for death by early changes
in markers of organ function, damage, and congestion
Metra M, et al. J Am Coll Cardiol 2013;61:196-206.
24. Significant Improvements in Biomarkers
*p 0.05, **p 0.005, and ***p 0.001 by repeated-measures ANOVA with adjustment for baseline value.
Metra M, et al. J Am Coll Cardiol 2013;61:196-206.
27.2
16.5
Percent of patients with
hs-cTnT increase
Placebo Serelaxin
0
5
10
15
20
25
30
p = 0.0001
23.2
16
Percent of patients with
>0.3 Cys-C increase
Placebo Serelaxin
0
5
10
15
20
25
p = 0.0027
58
69
Percent of patients with NT-
proBNP decrease ≥30%
Placebo Serelaxin
0
20
40
60
80
100
p = 0.0002
25. Serelaxin Trial Program
• RELAX-AHF-2 (NCT01870778): ~6,800 pts with
AHF;
1° endpoint: CV Death, Worsening Heart Failure
• RELAX-AHF-ASIA (NCT02007720): ~1520 pts
with AHF;
1° endpoint: Trichotomous clinical composite
• RELAX-Repeat (NCT01982292): ~300 pts with
CHF;
repeat administration q 4 wks for 3 doses;
Safety and tolerability, efficacy
28. Kanu Chatterjee, MBBS,
FRCP, FCCP, FACC,
MACP
March 1, 1934-March 4,
2015“Quiet, modest, and endlessly
proud of the many young
physicians he had inspired and
trained, he changed the
practice of cardiology in the
world.”
In honor and memory of…
