Nuove prospettive nel trattamento

dello scompenso acuto

Michele Emdin,
Fondazione Gabriele Monasterio, Pisa

Congresso regionale ANMCO Toscana,

Viareggio, 7 OTTOBRE 2011

Acute Heart Failure

Syndrome(s)
Acute heart failure (AHF) is defined as a
rapid onset or change in the signs and
symptoms of HF, resulting in the need for
urgent therapy.
Symptoms are primarily the result of severe
pulmonary congestion due to elevated left
ventricular (LV) filling pressures (with or
without low cardiac output).
AHFS can occur in patients with preserved or
reduced ejection fraction (EF).
Concurrent cardiovascular conditions such as
coronary heart disease (CHD), hypertension,
valvular heart disease, atrial arrhythmias,
and/or noncardiac conditions (including renal
dysfunction, diabetes, anemia) are often
present and may precipitate or contribute to
the pathophysiology of this syndrome

AHFS: NOT VERIFIED

EBM in AHFS?

The first randomized placebo-controlled AHFS

trials were published as late as 2002.
Cuffe MS, et al. for the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure
(OPTIME-CHF) Investigators. Effects of short-term, intravenous milrinone on acute exacerbation of chronic heart failure: a
randomized controlled trial. JAMA. 2002; 287: 15411547.

Publication Committee for the VMAC Investigators. Intravenous nesiritide vs nitroglycerin for treatment of decompensated
congestive heart failure: a randomized controlled trial. JAMA. 2002; 287: 15311540

None of the placebo-controlled AHFS studies

conducted to date has shown either a
consistent improvement of in-hospital or
postdischarge survival or a decrease in
readmissions.

AHFS Goals of
treatment
Emergency treatment phase

Improve symptoms
Restore oxygenation
Improve organ perfusion and haemodynamics
Limit cardiac/renal damage
Minimize ICU length of stay

In-hospital management phase

Stabilize patient and optimize treatment strategy

Initiate appropriate (life-saving) pharmacological therapy
Consider device therapy in appropriate patients
Minimize hospital length of stay
Discharge planning phase
Plan follow-up strategy
Educate and initiate appropriate lifestyle adjustments
Provide adequate secondary prophylaxis
Prevent early readmission
Improve quality of life and survival

AHFS: which appropriate

targets of therapy ?
Traditionally, reduction in pulmonary
capillary wedge pressure (PCWP)
and/or increase in cardiac output.
However, other therapeutic targets
may include blood pressure control,
myocardial protection,
neurohormonal modulation, and
preservation of renal function.

Treatment of AHFS
Patients
The emergency treatment
phase

Patient Selection and Treatment

Congestion at Rest
No
No

Low
Perfusion
at Rest Yes

Warm & Dry

PCWP normal
CI normal
(compensated)

Cold & Dry

PCWP low/normal
CI decreased

Yes

Warm & Wet

PCWP elevated
CI normal
Cold & Wet
PCWP elevated
CI decreased
Normal
SVR

Inotropic Drugs
Dobutamine
Milrinone
Calcium Sensitizers
Stevenson LW. Eur J Heart Fail. 1999;1:251.

High
SVR

Natriuretic
Peptide
Nesiritide
or
Vasodilators
Nitroprusside
Nitroglycerin

Recommended approach to the use of inotropic support in

patients hospitalized with acute HF exacerbation

Goldhaber, J. I. et al. Circulation 2010;121:1655-1660

Copyright 2010 American Heart Association

Adverse Drug Effects

Non-Potassium-Sparing Diuretics
Intravenous loop diuretics may improve symptoms and fluid loss
initially but also may contribute to renal function decline. This may be
related not only to intravascular volume depletion but also to further
neurohormonal activation resulting in a vasomotor nephropathy.
Intravenous loop diuretics may be associated with worse outcomes in
AHFS patients.
Inotropic Therapy
Intravenous inotropes increase myocardial oxygen consumption,
causing myocardial damage in the setting of hibernating myocardium.
Use of inotropes has consistently been associated with increased
mortality.
Vasodilators
Excessive vasodilatation in AHFS may lead to blood pressure decrease,
potentially exacerbating myocardial ischemia and renal hypoperfusion.

AHFS: which appropriate

targets of therapy ?
Perspectives
Managing fluids,
Preserving renal
function

Furosemide

Loop diuretics are an essential component of therapy for

patients with acute decompensated heart failure, but there are
few prospective data to guide their use.
In a prospective, double-blind, randomized trial, we assigned
308 patients with ADHF to receive furosemide administered
intravenously by means of either a bolus every 12 hours or
continuous infusion and at either a low dose (equivalent to the
patients previous oral dose) or a high dose (2.5 times the
previous oral dose).
Among patients with ADHF, there were no significant differences
in patients global assessment of symptoms or in the change in
renal function when diuretic therapy was administered by bolus
as compared with continuous infusion or at a high dose as

The study tests the hypothesis that in patients admitted with acutely
decompensated heart failure (ADHF), achievement of adequate body hydration
status with intensive medical therapy, modulated by combined bioelectrical
vectorial impedance analysis (BIVA) and B-type natriuretic peptide (BNP)
measurement, may contribute to optimize the timing of patients discharge and
to improve clinical outcomes.

300 ADHF pts underwent serial BIVA and BNP measurement. Therapy was
titrated to reach a BNP value of \250 pg/ml, whenever possible.

Our study confirms the hypothesis that combined BNP/BIVA sequential

measurementshelp to achieve adequate fluid balance status in patients with
ADHF and can be used to drive a tailored therapy, allowing clinicians to
identify high-risk patients and possibly to reduce the incidence of complications
secondary to fluid management strategies.

Uktrafiltratio
n

Rolofylline

Small studies have indicated that

adenosine A1 receptor antagonists
enhance diuresis and may improve
renal function in patients with
chronic heart failure or AHF.

2,033 AHF pts, volume overload,

eCrCl 20 - 80 ml/min, and elevated
BNP randomized (2:1) within 24 h of
hospital presentation to rolofylline
30 mg/day or intravenous placebo
for up to 3 days.

In this large, phase III clinical trial,

the adenosine A1 receptor
antagonist rolofylline did not
prevent persistent worsening renal
function in AHF patients with
volume overload and renal
dysfunction.

Rolofylline

Effects of rolofylline on endpoints in relation to baseline renal function.

The secondary morbidity/mortality endpoint, the risk of death or cardiovascular
or renal rehospitalization through day 60, was lower in the rolofylline group
compared with the placebo group only in patients with a baseline eCrCl 30
ml/min (hazard ratio: 0.64; 95% CI: 0.43 to 0.95), but not in the other subgroups

AHFS: which appropriate

targets of therapy ?

Contractility
Diastole

Istaroxime

Istaroxime is a novel intravenous agent with inotropic and lusitropic properties

related to inhibition of Na/K adenosine triphosphatase (ATPase) and stimulation
of sarcoplasmic reticulum calcium ATPase.
120 AHF pts and reduced systolic function. Three sequential cohorts of 40
patients each were randomized 3:1 istaroxime:placebo to a continuous 6-h
infusion. The first cohort received 0.5 g/kg/min, the second 1.0 g/kg/min, and
the third 1.5 g/kg/min istaroxime or placebo.
In patients hospitalized with HF, istaroxime improved PCWP and possibly
diastolic function. In contrast to available inotropes, istaroxime increased SBP

Urocortins

Urocortins are a recently discovered group of peptide hormones of the

corticotropin releasing factor family. They bind with a strong affinity to
the CRH-R2 receptor, which is highly expressed in the myocardium and in
the vascular endothelium.
Urocortins exhibit potent inotropic and lusitropic effects on rat and sheep
hearts and activates a group of myocyte protective pathways collectively
known as reperfusion injury salvage kinase.
In healthy humans show that brief intravenous infusions of urocortin 2 in
healthy humans induce pronounced dose-related increases in cardiac
output, heart rate, and left ventricular ejection fraction while decreasing
systemic vascular resistance; similar effects were seen in HF patients.

AHFS: which appropriate

targets of therapy ?

Vasomotion

Nesiritide

Nesiritide is approved in the United States for early relief of dyspnea in

patients with acute heart failure. Previous meta-analyses have raised
questions regarding renal toxicity and the mortality associated with
this agent.

We randomly assigned 7141 patients

Coprimary end points were the change in dyspnea at 6 and 24 hours,

and the composite end point of rehospitalization for heart failure or
death within 30 days.

Nesiritide was not associated with an increase or a decrease in the rate

of death and rehospitalization and had a small, nonsignificant effect on
dyspnea when used in combination with other therapies.
It was not associated with a worsening of renal function, but it was
associated with an increase in rates of hypotension. On the basis of
these results, nesiritide cannot be recommended for routine use in the
broad population of patients with acute heart failure.

Chimeric natriuretic peptides

These molecules have been engineered to combine the beneficial aspects

of different natriuretic peptides into a single molecule while minimizing
potentially negative actions.
CD-NP is a combination of C-type natriuretic peptide (CNP) and
Dendroapsis NP
(DNP).
Although lacking natriuretic effects, CNP is a more selective venodilator
than BNP, thus reducing the risk of significant hypotension. On the other
side, DNP possesses significant natriuretic activity, at the expense of
possible hypotensive effects.
The chimeric peptide CD-NP combines the favourable natriuretic effects of
DNP with the venodilatory profile of CNP, reducing the risk for harmful
side effects.

Cinaciguat

Cinaciguat (BAY 58-2667) is a soluble guanylate cyclase (sGC, second

messenger that internalizes the message carried by intercellular messengers
such as peptide hormones and NO) activator that is being developed as a firstin-class treatment for acute decompensated heart failure (ADHF). It acts
independently of the sGC ligand nitric oxide.

Cardioprotective effects in animal models, and pilot clinical studies found that it
was well tolerated, unloaded the heart and increased cardiac output.

This placebo-controlled, randomized, double-blind, multicenter, international

phase IIb study investigated the safety and efficacy of intravenous cinaciguat
(per-protocol) as add-on to standard therapy in 139 patients with ADHF (NYHA
functional class III and IV; pulmonary capillary wedge pressure [PCWP] 18
mmHg).

Cinaciguat rapidly and significantly reduced PCWP and PVR and increased
cardiac output in patients with ADHF, without impairing cardiac or renal

Acadesine

Adenosine regulating agents

This new class of drugs, whose prototype is represented by acadesine,
has been developed to mimic the protective effects of adenosine during
ischaemia.
Acadesine exerts its pharmacological actions by increasing adenosine
bioavailability and by activating 50adenosine monophosphate (AMP)
signalling cascade via its metabolite 5-aminoimidazole-4-carboxamide
riboside (ZMP).
The first mechanism leads to multiple anti-ischaemic effects
(maintenance of endothelial function and vasodilation, inhibition of
platelet aggregation and neutrophil activation), whereas the latter
ameliorates glucose uptake and free fatty acid oxidation thus increasing
ATP synthesis. Importantly, acadesine exerts its actions only in areas
undergoing net ATP catabolism (such as ischaemic tissues) thereby

Relaxin

First identified as a pregnancy hormone with powerful

vascular effects, relaxin is currently under investigation
for its systemic and renal vasodilatory actions.
In AHFS patients with high SBP, data from a Phase II trial
have demonstrated an improvement in dyspnoea with a
single dose.
A Phase III clinical trial is currently underway.

In-Hospital Management
Phase
This phase begins once the patient is stabilized
and dyspnea is improved.
Because a significant number of patients
continue to have signs and symptoms of HF, the
goals of this phase are continued hemodynamic
and symptomatic improvement while preventing
myocardial and renal injury.
Patients who are not treated with ACE inhibitors,
angiotensin receptor blockers, -blockers, or
aldosterone antagonists should receive these
therapies, as recommended by recent guidelines

AHFS: in-hospital
management
(ADHERE/OPTIMIZE-CHF/EURO-HF)

Discharge-Planning
Phase
Despite the clinical evidence supporting the
use of implantable cardiac defibrillators and
cardiac resynchronization therapy in patients
with chronic HF and systolic dysfunction,
their role in AHFS patients is not clear.
The available data suggest that a significant
number of AHFS patients are not being
evaluated for potential beneficial surgical
procedures that include myocardial
revascularization, LV reconstruction, mitral
valve surgery, or cardiac transplantation.

AHFS where are we? Where are we

going?
AHFS is a complex condition with substantial morbidity and
mortality and enormous utilization of health resources and
cost.
There are numerous challenges in caring for this
population.
Uniform AHFS classification is currently lacking, and
management strategies vary markedly.
There is a general consensus that to reduce mortality,
morbidity, and the economic burden of AHFS, systematic
research efforts on clinical application and translation of
promising basic science results are needed.
Pathophysiologically based interventions (eg, cardiorenal
syndrome) may be particularly appealing.
A special focus should be on choice of appropriate
management strategies, including minimizing the use of
drugs with adverse effects and development and validation
of known prognostic markers to guide AHFS interventions.

of note, every large published clinical trial

conducted in patients with AHFs has been
negative in terms of efficacy, safety, or both.
However, most international multicenter clinical
trials completed to date were conducted on fairly
undifferentiated populations of patients with
AHFs.
.homogeneous pathophysiological disease
states within the heterogeneity of aHFs is of
paramount importance to clinical trial design and
aHFs therapy.
Future trials conducted in aHFs must abandon
the one-sizefits- all approach in favor of an
approach that takes into account the varied and
distinct pathophysiologies of aHFs.

Milton Packer 2008 JCF

Yet, despite substantial advances in our

understanding and management of heart failure, we
have had
few successes and many failures.
Nearly 1,000 new drugs and devices have been
developed for the treatment of heart failure duringthe
past 20 years, but only 9 have received regulatory
approval and are being used in the clinical setting.
Most of our efforts to correct fluid retention, stimulate
the inotropic state of the heart, and modulate
neurohormonal systems have not predictably improved
the condition of patients with HF

Artwork
by
Ursula
ferrara

Michele Emdin, emdin@ftgm.it

Apelin

Effects of
Nesiritide
Venous, arterial, coronary
VASODILATION

RENAL

HEMODYNAMIC

NATRIURESIS
DIURESIS

CARDIAC
INDEX

rhBNP

R I SS
D
S
M
S
K
G
R
L
G
H
G
F
R
C
R
S
S
C
K V L
G
S P K MV
QGS

Preload
Afterload
PCWP
Dyspnea

Fluid volume
Preload
Diuretic
usage

Aldosterone
Endothelin
Norepinephrine

CARDIAC
No increase in HR
Not proarrhythmic

SYMPATHETIC AND
NEUROHORMONAL SYSTEMS