Acute heart failure: diagnosing and managing acute heart failure in adults
Serelaxin in acute heart failure
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Transcript of Serelaxin in acute heart failure
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
16.March, 2015
San Diego, CA
UC SF
Treatment Strategies for Hospitalized Heart Failure Patients:
Should We All RELAX?
Serelaxin in Acute Heart Failure
Treatment Strategies for Hospitalized
Heart Failure Patients
Improve Cardiac Performance without Serious
Adverse Effects
• Nitroxyl donors (CXL-1427)1
• Cardiac myosin activators (Omecamtiv mecarbil)2
1 Sabbah HN, et al. Circ Heart Fail. 2013;6:1250-58. Gheorghiade M, et al. Eur J Heart Fail. 2013;15:679–89. 2 Teerlink JR, et al. Lancet. 2011;378: 667–75. Cleland JGF, et al. Lancet. 2011;378: 676–83.
Treatment Strategies for Hospitalized
Heart Failure Patients
Vasodilators with Demonstrated Clinical Benefits
• TRV027: Angiotensin Type 1 receptor biased-ligand 1
• Ularitide: synthetic urodilatin 2
• Serelaxin: recombinant human relaxin-2
(Pre-RELAX-AHF; RELAX-AHF) 3
1 Soergel D, et al. J Clin Pharmacol. 2013;53:892-9. 2 Mitrovic V, et al. Am Heart J. 2005;150:1239. Mitrovic V, et al. Eur Heart J. 2006; 27:2823–32. 3 Teerlink JR, et al. Lancet. 2009; 373: 1429–39. Teerlink JR, et al. Lancet. 2013;381:29-39.
Treatment Strategies for Hospitalized
Heart Failure Patients
Vasodilators with Demonstrated Clinical Benefits
• TRV027: Angiotensin Type 1 receptor biased-ligand 1
• Ularitide: synthetic urodilatin 2
• Serelaxin: recombinant human relaxin-2
(Pre-RELAX-AHF; RELAX-AHF) 3
1 Soergel D, et al. J Clin Pharmacol. 2013;53:892-9. 2 Mitrovic V, et al. Am Heart J. 2005;150:1239. Mitrovic V, et al. Eur Heart J. 2006; 27:2823–32. 3 Teerlink JR, et al. Lancet. 2009; 373: 1429–39. Teerlink JR, et al. Lancet. 2013;381:29-39.
• Insulin-like protein
• Naturally-occurring peptide
• Found in men and women
• Normal hormone of pregnancy
• Women “exposed” for 9 months to
increased plasma concentrations:
0.8-1.6 ng/ml pregnancy*
• Benign safety profile
Relaxin
*Szlachter et al. Obstet & Gynecol 1982;59:167-70; Stewart et al. J Clin Endocrinol Metab 1990;70:1771-3.
Relaxin
• 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)
*Selective dilation of pre-constricted vessels; AHF=acute heart failure; ECM=extracellular matrix; ET-1=endothelin-1; GFR=glomerular filtration rate; NO=nitric oxide; RBF=renal blood flow; SVR-systemic vascular resistance
Serelaxin has potential multi-mechanistic effects which may address
the pathophysiology of AHF
Serelaxin
Adapted from Du et al. Nat Rev Cardiol 2010;7:48–58
Remodeling
↓ Fibrosis
↑ ECM remodeling 3
↑ Matrix
metalloproteinases
↓ Vessel stiffness
↓ Collagen synthesis
↑ Collagen breakdown
↑Tissue healing
↓ Inflammation
↑ Cell survival
↑ Cell preservation 2
↓ Inflammatory cell
infiltration
↓ Oxidative stress
↑ Angiogenesis
↑ Stem cell survival
↓ Oxidative stress
↓ Apoptosis
↓ Ca2+ overload
↓ Infarct size
Vasorelaxation*
↓ Myocardial overload; ↑
Renal function 1
↑ Endothelial NO*
↓ SVR, ↑ RBF, ↑ GFR
↓ ET-1
Volume redistribution
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
*p=0.04 vs placebo
*
Pre-RELAX-AHF:
CV Deaths to Day 180 Serelaxin 30 μg/kg/d*
Serelaxin 10 μg/kg/d
Serelaxin 100 μg/kg/d
Serelaxin 250 μg/kg/d
Placebo
Teerlink JR, et al. Lancet 2009;373:1429–1432.
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
Visual Analog Scale
• Absolute assessment of dyspnea & WHF/ death
• Endpoint: AUC over 5 days 100 = Best breathing
90
80
70
60
50
40
30
20
10
0 = Worst breathing
Likert Scale
3 = Markedly better
2 = Moderately better
1 = Minimally better
0 = No change
-1 = Minimally worse
-2 = Moderately worse
-3 = Markedly worse
• Relative assessment of dyspnea
• Endpoint: moderate/marked improvement at each of 6,12, and 24h
1°Endpoint: VAS and Likert Instruments
Teerlink JR, et al. Lancet 2013; 381:29-39.
0
10
20
30
40
50
60
70
80
6 hr 12 hr 24 hr 6, 12, and 24 hr
PlaceboSerelaxin
p=0.086
p=0.051
p=0.113
p=0.702
n=150 n=156 n=205 n=180 n=256 n=288 n=362 n=389
Proportion of subjects with moderately or markedly better dyspnea by Likert by time point
p value by Chi-square test
1°Endpoint: Dyspnea Relief (Likert)
Teerlink JR, et al. Lancet 2013; 381:29-39.
0.0
0.5
1.0
1.5
2.0
2.5
Dyspnea Assessment by Likert:
Time to Moderately/ Markedly Improved Dyspnea
p = 0.002
n=580 n=581
Placebo Serelaxin
1.91
(1.74, 2.08)*#
1.53
(1.38, 1.68)*#
Mea
n T
ime
to M
od
erat
e o
r M
arke
dly
Imp
rove
d D
ysp
nea
th
rou
gh
Day
5
(Day
s)
*p-value is based on a Wilcoxon rank test; # Mean (95% CI)
Visual Analog Scale
• Absolute assessment of dyspnea & WHF/ death
• Endpoint: AUC over 5 days 100 = Best breathing
90
80
70
60
50
40
30
20
10
0 = Worst breathing
Likert Scale
3 = Markedly better
2 = Moderately better
1 = Minimally better
0 = No change
-1 = Minimally worse
-2 = Moderately worse
-3 = Markedly worse
• Relative assessment of dyspnea
• Endpoint: moderate/marked improvement at each of 6,12, and 24h
1°Endpoint: VAS and Likert Instruments
Teerlink JR, et al. Lancet 2013; 381:29-39.
Clinical events supersede symptoms at the time of their occurrence
Visual Analog Scale Area Under the Curve:
Dyspnea Clinical Composite
Death In-hospital
worsening heart failure
Change in dyspnea score
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
0
5
10
15
20
25
30
35
0 1 2 3 4 5
AUC with placebo, 2308 ± 3082
AUC with serelaxin, 2756 ± 2588
p=0.0075
Ch
ang
e fr
om
bas
elin
e (m
m)
19.4% increase in AUC with serelaxin
from baseline through day 5
(Mean difference of 448 mm-hr)
Days 6
Serelaxin Placebo
12 hrs
1° Endpoint: Visual Analog Scale Area Under the Curve Composite
Teerlink JR, et al. Lancet 2013; 381:29-39.
**HR 0.7 (0.51, 0.96); p=0.024
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
(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
18
Teerlink JR, et al. Lancet 2013; 381:29-39.
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=0.003
Primary Endpoint Sensitivity Analyses
Based on Clinically Ranked Outcomes
P value
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)
Fewer Serelaxin Treated Patients Required IV
Diuretics, Vasodilators, Inotropes and Mechanical Support
0
50
100
150
200
250
N=572 N=570 IV d
iure
tics
use
(cum
ulat
ive
to
tal d
ose
from
day
1-5
[mg]
)
*p=0.006
Placebo Serelaxin
24% difference
Less use of IV diuretics in serelaxin
group
0
20
40
60
80
100
N=580 N=581
Pat
ient
s tr
eate
d w
ith IV
vas
odila
tors
, In
otro
pes
or M
echa
nica
l Sup
port
(n)
*p=0.017
Placebo Serelaxin
30% difference
16.4%
11.5%
Less use of IV Vasodilators, Inotropes and
Mechanical Support in serelaxin group
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
0
1
2
3
4
5
Placebo Serelaxin
0
2
4
6
8
10
12
Placebo Serelaxin
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
Len
gth
of
Sta
y (D
ays)
ICU
/CC
U S
tay
(Day
s)
Teerlink JR, et al. Lancet 2013; 381:29-39.
Dyspnea Relief (VAS AUC Day 5) CV Death Through 180 Days
Metra M, et al. Eur Heart J 34:3128-36.
Early changes from baseline in laboratory values
*p 0.05, **p 0.005, and ***p 0.001 by repeated-measures ANOVA with adjustment for baseline value.
27.2
16.5
0
5
10
15
20
25
30
Placebo Serelaxin
Percent of patients with hs-cTnT increase
p = 0.0001
Metra M, et al. J Am Coll Cardiol 2013;61:196-206.
23.2
16
0
5
10
15
20
25
Placebo Serelaxin
Percent of patients with >0.3 Cys-C increase
p = 0.0027
*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.
Early changes from baseline in laboratory values
58
69
0
20
40
60
80
100
Placebo Serelaxin
Percent of patients with NT-proBNP decrease ≥30%
p = 0.0002
*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.
Early changes from baseline in laboratory values
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.
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
Sur
viva
l pro
babi
lity
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.
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
No time to relax!
Kanu Chatterjee, MBBS, FRCP
(London and Edin), 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.”
San Francisco Veterans Affairs Medical Center
Thank you!