vasodilatadores na insuficiÊncia cardÍaca aguda - o … · susana r. martins serviço de...
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Susana R. Martins
Serviço de Cardiologia, Hospital de Santa Maria
Centro Hospitalar Lisboa Norte, EPE
VASODILATADORES NA INSUFICIÊNCIA
CARDÍACA AGUDA - O ETERNO DESAFIO
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Is the term used to describe the rapid onset, or
changing, symptoms and signs of HF.
It is a life threatening condition that requires immediate
medical attention
In most cases, AHF arises as a result of deterioration in
patients with previous diagnostic of HF. In these
patients there is often a clear precipitant or trigger.
AHF – definition
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AHF IS NOT A SINGLE DISEASE, BUT
RATHER A HETEROGENEOUS FAMILY OF
CLINICAL SYNDROMES, EACH WITH
DISTINCT CLINICAL PRESENTATION,
PROGNOSIS AND MANAGEMENT
AHF – definition ???
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CHARACTERISTICS OF PATIENTS WITH DE
NOVO HF AND ADCHF: EUROHF-II
Variable, % of pts. ADCHF
(n=2251)
De novo HF
(n=1235)
P value
Males 64 57 <0.001
Renal failure 20 11 <0.001
Dilated cardiomyopathy 25 9.5 <0.001
History of CHD 62 39 <0.001
Acute coronary syndrome
STEMI
NSTEMI
23
6
7
42
20
25
<0.001
<0.001
<0.001
Nieminen et al., Eur Heart J 2006; 27, 2725–2736
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Number of diagnosed events of AHF by country, 2004–2014
Acute Heart Failure, December 2005. Decision Resources, Inc. 2005
Acute heart failure worldwide
2004 2009 2014
Growth
(millions)
2004–2009
Growth
(%/year)
2009–2014
USA 4,137,700 4,556,200 5,021,400 1.9 2.0
Europe 3,191,400 3,485,800 3,774,200 1.8 1.6
France 464,500 512,000 558,300 2.0 1.7
Germany 856,100 949,300 1,045,100 2.1 1.9
Italy 548,000 596,300 638,800 1.7 1.4
Spain 312,500 344,600 374,000 2.0 1.7
UK 1,010,400 1,083,600 1,157,900 1.4 1.3
Japan 799,500 810,200 811,600 0.3 0.0
Total 8,128,700 8,852,000 9,607,200 1.7 1.7
AHF is growing at 1.7% per year
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Events usully leading to rapid deterioration
Rapid arrhythmia or severe bradicardia/conduction
disturbance
ACS
Mechanical complication of ACS
Acute pulmonar embolism
Hypertensive crisis
Cardiac tamponade
Aortic dissection
Surgery and perioperative problems
Peripartum cardiomyopathy
PRECIPITANTS AND CAUSES OF AHF
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Events usully leading to less rapid deterioration
infection
COPD/Asthma
anaemia
Kidney dysfunction
Non adherence to diet and drug theraphy
Iatrogenic causes (NSAID, corticosteroid
Uncontrolled hypertension
Hypo or hyperthyroidism
Alcohol and drug abuse
PRECIPITANTS AND CAUSES OF AHF
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Does the patient have AHF or is there an alterative cause for SS (anaemia, kidney failure, pulmonary embolism?)
If is HF, is there a precipitant and does it require immediate R/ (ACS, arrhythmia)?
Is condition immediately life-threatening because of hypotension or hypoxaemia leading to underperfusion of vital organs ?
INITIAL ASSESSMENT AND MONITORING
3 PARALLEL ASSESSMENTS IN INITIAL EVALUATION
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Suspected AHF
Hystory/examinatio
Chest X.ray
ECHO,
LAB
ECG
O2 saturationn
Ventilation/Oxygenation inadequate
O2, NIV, Invasive V
Arrhythmia/bradicardia
CVE. Pacing
BP< 85 mmHg or shock
Inotrope/vasopressor.
IABP
ACS
Coronary reperfusion
Antithrobotic theraphy
Acute mechanical cause/valvular disease
Echo
Surgical/percutaneous intervention
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ACUTE HEART FAILURE
Rudiger, Eur. J. Heart Fail., 2005
62%
24% 25%
36%
15%
4%
13%
Aetiology Trigger Presentation
Ischaemic Valvular Ischemia Elevated
BP
New AF Cardiogenic
shock
Pulmonary
Edema
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IN HOSPITAL MORTALITY
29%
5,5% 7%
18%
8%
4%
PHILBIN
1997
COWIE
2002
RUDIGER
2005
EHFS I
2003
EFICA
2003
FONAROW
2005
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SHORT-MEDIUM TERM MORTALITY
PHILBIN
1997
EHFS I
2003
EFICA
2003
RUDIGER
2005
6 months 12 weeks 1 year 30 days 1 year
22 %
13 %
51 %
11 %
29 %
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Unknown (10%)
Non CV (12%)
Other CV (5%)
Stroke (3%)
AMI (3%)
Sudden Cardiac Death (27%)
Heart Failure
(40%)
Adjudicated Cause of Death after Discharge in 4,133 Pts
Hospitalized with Worsening HF and low EF:
Over-all mortality rate of 26% at 10 months follow-up
O’Connor et al. ESC 2008
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LENGTH OF STAY
11
5,9
8
11
16
Euro Heart
Failure 2003
FONAROW
2005
RUDIGER
2005
EFICA
2005
Da
ys
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ACUTE HEART FAILURE
COMORBIDITIES
29%
54%
32%
41%
34%
AF HTA Diabetes Renal
Failure Anemia
Rudiger, Eur. J. Heart Fail., 2005
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AHFS and Progression of HF : a major
clinical challenge C
ard
iac
and
/or
Ren
al F
un
ctio
n
Hospitalization
Hypothesis: with each
hospitalization, there is
myocardial and or renal
damage
Gheorghiade M et al. Am J Cardiol. 2005; 96 (6A)
Hospitalization
Hospitalization
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Improve haemodynamics, diuresis and
neuroendrocine system
Clinical improvement, quality of life and/or
mortality
Safety
AIM FOR TREATMENT IN AHF
EMEA - EUROPEAN AGENCY for the EVALUATION of
MEDICINAL PRODUCTS
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CURRENT TREATMENTS FOR ACUTE
HF
Diuretics
Reduce
Fluid
Volume
Vasodilators
Decrease
Preload
And/or
Afterload
Inotropes
Augment
Contractility
Each of these agents has their own limitations
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None of Vasodilators currently used has been examined by large,
placebo controlled, prospective randomized studies.
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Peripheral vasoconstriction
Myocardial injury
Fluid retention
Cardiac arrhythmias
CENTRAL ROLE OF
VASOCONSTRICTION
Interaction between a progressive decrease in cardiac performance
and an acute increase in SVR, so called “afterload mismatch”
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Venous vasoconstriction
Arterial vasoconstriction
INCREASED VENOUS PRESSURE
• Peripheral edema
• Redistribution of peripheral venous blood into pulmonary vasculature
• Pulmonary edema
• Increased preload
• REGIONAL ARTERIAL VASOCONSTRITION
• Increase afterload
• Increase myocardial workload
• Increase myocardial wall tension
• Regional arterial vasoconstriction
• Renal failure
• Cerebral hypo perfusion
• ACS
• Stimulation of chronic vascular remodeling
CENTRAL ROLE OF VASOCONSTRICTION IN PATHOGENESIS OF AHF
about 90% pts have BP normal / high at admission
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Vasoconstrictor systems
Sympathetic
Renin-angiotensin
Aldosterone
Endothelin
vasopressin
Vasodilators systems
Bradykinin
Nitric oxide
Prostacyclin
Natriuretic peptides
NEUROHORMONAL PLAYERS IN
HF
Powerful neurohormones vasoconstrictor forces dominates
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Vasodilation (venous and arterial)
Rapidly decreases ventricular filling pressures and congestion
Does not increase heart rate or directly increase contractility (decreases
myocardial oxygen demand)
Is not proarrhythmic
Has no tachyphylaxis
Provides neurohormonal suppression
Promotes diuresis/natriuresis
Is conveniently dosed (can be used with or without pulmonary artery
catheterization)
Minimal titration needed
Ideal Agent for AHF treatment The Saint Graal ?
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POTENTIAL RISKS AND BENEFITS OF VASODILATORS IN AHF
Makes patients feel better, early and sustained relief of dyspnea
Possibility of hypotension, worsening renal function, myocardial damage.
May cause “coronary steal” and be harmful in pts with ongoing ischemia
May have a U-shaped dose-effects relationships, high doses may reduce
their effectiveness , because of counter regulatory mechanisms, induce
rebound neurohormonal activation pottentially limiting short and long
term efficacy
In pts with AHF with reduced cardiac reserve, vasodilators nay induce a
steep reduction in BP, inappropriate vasodilatation, ischemia, renal failure
and sometimes shock,.
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Used for more than 100 years
Biotransformation mainly in the smooth muscle intracellular
space, leading to formation of ON or a related S-nitrosothiol,
which stimulates guanylate cyclase
Reduces intracellular calcium levels which leads to venous and
arterial vasodilatation
Promotes endothelial production of prostacyclin
ORGANIC NITRATES
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Nitroglycerine and ISD
TRADITIONAL VASODILATORS
European Heart J 2008
Exerting a predominant venodilator effect at low doses
and mild arteriolar effect at higher doses
R & LVF pressures, PVR, SVR, wall stress, pulmonary congestion,
without compromising stroke volume or
increasing myocardial oxygen consumption
Decrease BP, but little or no change in HR
Reduces Mitral Regurgitation
AHF without Hypotension class I, B
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Reduction OF plasma natriuretic peptide BUT small increase
aldosterone, cortisol, epinephrine and plasma renin
Dilatation of main renal artery
Early development of tolerance and marked attenuation of initial
hemodynamic effects in half pts with AHF
ORGANIC NITRATES:
NEUROHORMONAL EFFECTS
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Careful monitoring of BP
High doses may reduce effectiveness because of counter regulatory
mechanisms
TRADITIONAL VASODILATORS
European Heart J 2008
Use with caution in pts who really deserve them, using right doses,
monitoring and carefull titulation
AHF without Hypotension
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Salt of complex molecule made up of ferric cyanide
Production of nitrosothiol and GMPc in vascular smooth muscle
Reduces elevated filling pressures, increase venous capacitance
Reduces afterload of right and LV
Significant reduction in BP, RAP, PCWP, SVR and PVR. Increase
CO
Effect on coronary blood flow in pts with CAD may be
determinated by more vasodilatory effect on nonobstructed
coronary beds
NITROPRUSSIDE
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VASODILATORES TRADICIONAIS:
Nitroprussiato, class IC
Difícil titulação, (± linha arterial)
Resposta neuro-hormonai; Aumento NE, renina,
Potente vasodilatador arterial e venoso
Pequenos estudos Melhoria hemodinâmica
SEC 2008
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Treatment of ADHF and Acute Valvular Regurgitation.
Can cause rebound effects-gradual discontinuation
Can effectively augment hemodynamic effects of inotropic agents.
The incidence of side effects and toxicity is dose and duration related
Side effects of thiocyanate toxicity (> 6 mg): metabolic acidosis- can be
removed by hemodialisis and treated with hydroxycobalamin
Conversion of cyanide to prussic acid incresase methemoglobin levels
These effects are rare if we use NTP < 3 ng/Kg/min e < 72 hours
NITROPRUSSIDE
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Drug Indication Regimen Adverse
effects
Limitations
nitroglycerine Acute PE;
pulmonary
congestion in
normo or
hypertensive
AHF
10-20 ug/min,
increase up to
200 ug/min
Hypotension
Headache
Tolerance is
common after
24-48 h,
requiring
adjustment of
dosing
ISD Pulomonary
Edema
Pulmonary
congestion
normo/HBP
1 mg/h, increase
up to 10 mg/h
Hypotension
Headache
Tolerance as for
nitroglycerine
Nitroprusside Acute
hypertensive
congestion due
to acute mitral
Regurgitation
0,3ng/Kg/min
Increase up to 5
mg/Kg/min
Hypotension
Isocyanate
toxicity
Light sensitive
Arterial line is
necessary for BP
monitoring
neseritide Pulmonary
edema
Pulmonary
congestion
Bolus and
perfusion 0,015-
0,030
ug/Kg/min
Hypotension
Worsening renal
function
Not available in
ESC countries
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rhBNP
D R I
M
K
R
G
S S
S
S
G
L
G F
C C
S S
G S G Q V M
K V L R
R H
K P S
ACTIONS OF HUMAN BNP ENDOGENOUS BNP IS AN ADAPTIVE RESPONSE TO PRESSURE AND VOLUME OVERLOAD
Venous, arterial, coronary
VASODILATION
CARDIAC
INDEX
Preload
Afterload
PCWP
Dyspnea
HEMODYNAMIC
CARDIAC
No increase in HR
Not proarrhythmic
Aldosterone
Endothelin
Norepinephrine
SYMPATHETIC AND
NEUROHORMONAL
MODULATION
NATRIURESIS
DIURESIS
Fluid
volume
Preload
Diuretic
usage
RENAL
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Nesiritide (h-BNP) is identical to the endogenous naturally occurring hormone, with identical pharmacological
profile
32 amino acid sequence
Recombinant technology using E-coli
D R I
M
K
R G
S S
S
S
G
L
G F
C C
S S
G S G Q V M
K V L R R
H
K P S
NOTE: hBNP affects assay for BNP, but can still use proBNP or one of the proANP assays
The serum half-life of iv nesiritide is
18 minutes, but attenuation of
hemodynamic effects is not seen
until 2 h after discontinuation of
infusion and may persist for up to 4 h
Metabolism of nesiritide is not
affected by renal or hepatic
dysfunction
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Intravenous Nesiritide versus Nitroglycerin for the Treatment of
Decompensated Heart Failure – VMAC trial
Dyspnea Pulmonary Wedge Pressure
-10
-8
-6
-4
-2
0
0 1 2 3 Time, h
Mean c
hange,
mm
Hg
Placebo (n=142)
Nitroglycerin (n=143)
Nesiritide (n=204)
* * +
* +
* + * +
* +
-40
-20
0
20
40
60
80
100
Pro
po
rtio
n o
f patients
, %
Nesiritide
P=.56
P=.03
Placebo Nitroglycerin
P=.19
Markedly better Moderately better
Minimally better
Minimally/markedly worse No change
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Dyspnea Improvement in VMAC VMAC -
Nesiritide
Critical look – minimal
dyspnea improvement
With worsening renal
function and increased
mortality
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Sackner-Bernstein JD, et al. JAMA. 2005;293:1900-1905.
0
2
4
6
8
10
0 10 20 30
Mort
alid
ade, %
Dias
Nesiritide
(n = 485)
Control
(n = 377)
Unadjusted: hazard ratio 1.86 (95% CI, 1.02-3.41), P=0.04
Adjusted for study: hazard ratio 1.80 (95% CI 0.98-3.31), P=0.057
Meta-Análise de 3 ensaios com Nesiritide*
*NSGET, VMAC, and PROACTION trials
EFEITO DO NESIRITIDE NA MORTALIDADE
A CURTO PRAZO (30 DIAS)
Sugere que nesiritide aumenta a mortalidade a curto prazo
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Acute Study of Effectiveness
of Nesiritide in Decompensated
Heart Failure
Adrian F. Hernandez, MD
On behalf of the ASCEND-HF Committees,
Investigators and Study Coordinators
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ASCEND-HF design
completed in 2010
# 7000 pts enrolled
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Double – blind placebo controlled
IV bolus (loading dose) of 2 µg/kg nesiritide or placebo
• Investigator’s discretion for bolus
• Followed by continuous IV infusion of nesiritide 0.01 µg/kg/min or placebo for up to 7 days
Usual care per investigators including diuretics and/or other therapies as needed
Duration of treatment based on clinical improvement per investigator
Study design and drug procedures
Nesiritide
Placebo
24–168 hrs Rx Acute HF < 24 hrs
from IV RX
Co-primary endpoint:
Dyspnea relief
at 6 and 24 hrs
Co-primary
endpoint:
30-day death or
HF rehosp
All-cause
mortality
at 180
days
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Co-Primary outcome: 30-day all-cause mortality or HF rehospitalization
Placebo
Nesiritide
P=0.31
10.1 9.4
4 3.6
6.1 6
HF Rehospitalization
30-day Death/HF
Rehospitalization
30-day Death
0
2
4
6
8
10
12
Risk Diff 95 % CI -0.7 (-2.1; 0.7) -0.4 (-1.3; 0.5) -0.1 (-1.2; 1.0)
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Co-Primary Endpoint: 6 and 24 hour dyspnea
P=0.030 5
0 4
0 3
0 2
0 1
0 0
1
0 2
0 3
0 4
0 5
0 6
0
% S
ub
jects
3444
Placebo
3416
Nesiriti
de 6
Hours
P=0.007 7
0 6
0 5
0 4
0 3
0 2
0 1
0 0
1
0 2
0 3
0 4
0
% S
ub
jects
3398
Placebo
3371
Nesiriti
de 24
Hours Markedly Better
Minimally Worse
Moderately Better
Moderately Worse
Minimally Better
Markedly Worse
No Change
13.4 15.0
28.7 29.5
34.1 32.8
# #
27.5 30.4
38.6 37.8
22.1 21.2
# #
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RELAXIN, A NOVEL TREATMENT
FOR ACUTE HEART FAILURE- THE PRE-RELAX-AHF STUDY
John R. Teerlink, Marco Metra, G. Michael Felker,
Adriaan A. Voors, Piotr Ponikowski, Beth D. Weatherley,
Elaine Unemori, Sam L.Teichman, and Gad Cotter
on behalf of the
Pre-RELAX-AHF Investigators & Patients
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RELAXIN MECHANISMS OF ACTION
Naturally occurring peptide
Up-regulated in pregnancy and HF
Vasodilation…
Upregulation of ETB
Induction of NOS II/III
NO, cGMP effectors
…but actually an anti-vasocontrictor - Preferential dilates constricted
vessels
Anti-ischemic effects in animal models
Anti-inflammatory
Down-modulation of inflammatory cytokines linked to outcome in HF
(TNF-a, TGF-b)
Relaxin
46
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RELAXIN MECHANISMS OF ACTION
Vasodilation
NO, cGMP effectors
Induction of NOS II/III
Upregulation of endothelial endothelin type B receptor, which mediates vasodilation
Preferential dilation of constricted vessels
Relaxin-upregulated ETB receptors act as vasodilating ET-1 sink
Anti-inflammatory
Down-modulation of inflammatory cytokines linked to outcome in HF (TNF- , TGF- )
Other: Anti-ischemic, Anti-apoptotic, Anti-fibrotic
Relaxin Receptor LGR7
Teichman, SL, et al. Heart Fail Rev 2009; Dschietzig, T, et al. Pharmacol Therap 2006
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48
GLOBAL PHASE 2 IN ACUTE HEART FAILURE
Dyspnea (shortness of breath): Serial Likert and VAS to Day 14
Other AHF measures - Signs, symptoms, outcomes through Day 14 -
180
Safety, including renal dysfunction
Choose dose, endpoints, sample size, sites for pivotal P3 trials
“Acute Vascular Failure” subset of AHF:
- Dyspnea requiring hospitalization
- BNP/NT-pro-BNP > 350/1400 pg/mL
- Baseline BP > 125 mmHg
- Renal dysfunction (CrCl 30-75 mL/min)
Study
Endpoints &
Objectives
Patient
Population
Phase 2/3, Multicenter, Randomized, Double-Blind, Placebo-Controlled,
International Study
Randomized to placebo, 10, 30, 100, 250 μg/kg of relaxin (3,2,2,2,2) – 48 hr
iv infusion, on top of standard of care
234 patients, 54 sites, 8 countries
Study Design
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Dyspnea Improvement over Time
49
Day 5 Day 14
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
10000
Dy
sp
ne
a (
AU
C;
mm
*hr)
p=0.11
p=0.05
p=0.06
Placebo 10 30 100 250
Relaxin (mcg/kg/d)
Placebo 10 30 100 250
Relaxin (mcg/kg/d)
p=0.16
p=0.16p=0.15
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CV Death or Heart/Renal Failure
Re-hospitalizations to Day 60
0.8
0.85
0.9
0.95
1
0 30 60 90 120 150 180
Kapla
n-M
eie
r E
ve
nt-
free S
urviv
al (%
)
Days
Placebo
Relaxin 10 mcg/kg/d
Relaxin 100 mcg/kg/d
Relaxin 250 mcg/kg/d
Relaxin 30 mcg/kg/d(p<0.05)
Cardiovascular Deaths to Day
180
0.8
0.85
0.9
0.95
1
0 30 60 90 120 150 180
Kapla
n-M
eie
r E
ve
nt-
free S
urviv
al (%
)
Days
Placebo
Relaxin 10 mcg/kg/d
Relaxin 100 mcg/kg/d
Relaxin 250 mcg/kg/d
Relaxin 30 mcg/kg/d(p<0.05)
Critical look – Too good to be true? Lack of clear mechanism of action?
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soluble Guanylate Cyclase (sGC) Stimulators
and sGC Activators
sGC Fe(III) heme sGC Fe(II) heme
sGC Stimulator sGC Activator
Oxidative Stress
cGMP
NO
sGC Activator
NO-independent mode of action
Selective dilation of diseased or
oxidative
stress impaired blood vessels
sGC Stimulator
Amplifies protective effects of NO in the
cardiovascular system
Stasch/as/3
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4,35
5,04
5,59
6,04
5,37
3
4
5
6
7
Cardiac Output
L/m
in
PCWP
mm
Hg
BAY 58-2667 after
2h 4h 6h BL
FU
2h
BAY 58-2667 after
2h 4h 6h BL
FU
2h
Proof of Concept Study – Hemodynamic Results
24,7
20,7
18,2 16,9
19,0
10
15
20
25
30
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4,35
5,04
5,59
6,04
5,37
3
4
5
6
7
Cardiac Output
L/m
in
PCWP
mm
Hg
BAY 58-2667 after
2h 4h 6h BL
FU
2h
BAY 58-2667 after
2h 4h 6h BL
FU
2h
Proof of Concept Study – Hemodynamic Results
24,7
20,7
18,2 16,9
19,0
10
15
20
25
30
Critical look – (1) may increase risk of hypotension
(2) Will need very careful titration and patient selection, but for some
patients especially with endothelial dysfunction – may be very
helpful
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CONCLUSIONS
Vasodilators may be beneficial in AHF. However, this has never
been shown in prospective well-powered studies.
Vasodilators make pts feel bettter
•Can these effects be achieved without collateral damage to vital
organs such as kidneys, heart and brain ?
•Can these be achieved without leading to detrimentral effects on
readmission or death or even reduce these outcomes ?
•Are all vasodilators equal or are venous vasodilators or renal
vasodilators superior ?
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Multiple physiopathological mechanisms
Different clinical presentations / different diseases
Multiple effects of vasodilator therapy
We remain with:
Nitrates
Nitroprusside in patients without active ischemia
Need of other trials and drugs
AHF AND VASODILATORS
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AHF THERAPY 2013 – COMBINATION
THERAPY?
Diuresis Reno-
protection Vasodilatation
Inotrope
Vasoconstricted
Sys BP > 125 mmHg
Renal Impairment
(eGFR< 80 cc/min)
Low output
Sys BP < 125
mmHg
# Relaxin ?
(phase III)
# Direct
Soluble GC
Activators ?
(phase II)
Congestion
#Low dose
Loop Diuretics
(Phase III)?
# Vasopresin
Antagonists and low
dose
Loop diuretics
(phase II)?
# Cardiac
Myosin
Activators?
(Phase II)
# SERCA2A
Activators?
(phase I)
Adenosin
e A1
Antagonists
(Rolofyline)?
(phase III - II)
Low dose
Natriuretic
Peptides?
(Phase II)
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1. Patient heterogeneity
Substrate (ischaemic / non ischaemic, HT).
Trigger ( ACS, arrhythmias, Hypertension crisis).
Pathophysiology ( systolic vs diastolic HF / low vs high
BP).
2. Lack of standard comparator.
3. COMPLEXITY ? Endpoints, time points, dose
Why trials in AHF have failed ???
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SIMPLICITY IS THE ULTIMATE SOPHISTICATION.
(LEONARDO DA VINCI)