New therapies in acute decompensated heart failure

Nadine Gauthier, Anjali H. Anselm and Haissam Haddad

University of Ottawa Heart Institute, Division of Purpose of review
Cardiology, Ottawa, Ontario, Canada
Hospitalization and mortality rates associated with heart failure are persistently high.
Correspondence to Haissam Haddad, MD, FRCPC, This is due partly to aging of the population but mostly to delayed progress in the
FACC, University of Ottawa Heart Institute, Suite 145,
40 Ruskin Street, Ottawa, Canada K1Y 4W7 pharmacological treatment of decompensated heart failure. We will review the current
Tel: +1 613 761 5165; fax: +1 613 761 5212; recommendations and most recent advancement in the pharmacological treatment of
e-mail: hhaddad@ottawaheart.ca
acute decompensated heart failure while providing a systematic approach to the
management of this prevalent condition.
Current Opinion in Cardiology 2008, 23:134– Recent findings
140
Loop diuretics, nitrates and inotropes such as dobutamine and milrinone are the current
mainstay of acute heart failure management although their associated morbidity and
possible mortality have raised serious concerns. Recent vasoactive agents such as
Nesiritide, Tolvaptan and more recently the inotropic agent Levosimedan could offer
improved hemodynamics and congestive relief to patients in acute pulmonary edema.
Summary
Despite the promising results of these agents, further clinical trials are required prior to
their international approval as first-line therapy. Although we can be optimistic that these
vasoactive drugs might have favorable clinical outcomes and improve the intricate
management of decompensated heart failure, their associated mortality benefit remains
unclear and controversial.

Keywords
acute decompensated heart failure, cardiac sensitizers, novel therapies, vasoactive
therapies, vasopressin antagonists

Curr Opin Cardiol 23:134–140

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0268-4705

Introduction Pathophysiology
Heart failure is one the most prevalent diseases world- The pathophysiological triad of ADHF includes conges-
wide in hospitalized adults above 65 years of age [1]. tion, myocardial injury and cardiorenal syndrome (in
Aging of the population and improved survival from other Table 1). The most contributory factor is congestion
cardiac conditions increases morbidity and mortality from often caused by poor compliance to medication and diet
acute decompensated heart failure (ADHF) [2]. Despite as well as neurohormonal activation and renal dysfunction
the socioeconomic cost of ADHF and the probable from longstanding heart failure [7,8]. Congestion may
evolution in chronic, lifelong illness, there are limited result from slow progression of volume retention in
numbers of randomized clinical trials on new pharmaco- patients with chronic heart failure or from an acute
logical agents. Acute heart-failure syndromes arise from process such as myocardial ischemia. High biventricular
various pathophysiologies and represent a heterogeneous filling pressures contribute to volume and wall stress,
group of disorders [3,4]. worsening myocardial injury [8]. Studies of patients in
ADHF without myocardial infarction showed higher
The therapeutic target for decompensated heart failure levels of troponin T in 55% patients with pulmonary
has traditionally entailed improving hemodynamics while edema. This was an independent predictor of long-term
preserving organ function with diuretics, inotropes and mortality [9,10].
vasodilators, but the growing importance of preservation
of myocardium during the acute presentation is now The last proposed mechanism is the cardiorenal syndrome
setting new management goals [5,6]. exacerbated by neurohormonal stimulation. Increased
vasopressin levels induce fluid and sodium retention,
In this review we will briefly summarize the recent vasoconstriction and generation of more myocardial wall
clinical trials for the pharmacological management of stress with decreased contractility. The consequence is
ADHF while offering an approach to the available treat- impaired renal function, ongoing deterioration of the
ment options. heart-failure syndrome through worsening myocardial
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 Acute decompensated heart failure Gauthier et al. 135

Table 1 Clinical assessment of acute heart failure syndromes, view of the therapeutic approach [13]. The Canadian
adapted and modified [3] guidelines recommend a similar algorithm in the initial
Congestion therapy of the ADHF patient as seen in Fig. 2 [14].

þ

Adequate þ Dry and warm Wet and warm Current and novel therapies for acute
perfusion Orthopnea, rales decompensated heart failure
Abnormal valsalva
" Jugular venous pressure The mainstays of current management of ADHF include
Abdominojugular reflux diuretics, vasodilators and inotropes. Novel therapies are
Hepatomegaly a source of hope but the absence of short-term thera-

Dry and cold Wet and cold
# Pulse pressure Hepatomegaly peutic surrogates poses another challenge in evaluating
Cool extremities Ascites these new pharmacological agents.
Altered mentation Edema
Worsening renal
function Diuretics
Conventional loop diuretics remain the current recom-
mended therapy for management of fluid overload and
injury, and hibernating myocardium [4,11]. Clinical temporary relief of symptoms from both systemic and
presentation of ADHF may vary from mild pulmonary pulmonary congestion. Loop diuretics produce more
edema to cardiogenic shock (Table 2). significant natriuresis than nonloop diuretics but unfortu-
nately have several limitations including enhancing water
The management of ADHF has become challenging and loss via excretion of solute, resulting in impaired glomer-
requires individual tailoring. Without a therapeutic ular filtration [15]. As discussed elsewhere, activation of
regimen that integrates improved hemodynamics and the renin–angiotensin cascade will lead to worsening fluid
preservation of myocardium, the perfect storm is inevi- overload and myocardial injury [10,16].
table [12].
Diuretic resistance is a clinical state previously identified
in chronic or decompensated heart failure patients on
Current recommendations long-term diuretic therapy. Intravascular depletion,
Recent guidelines from the European Society of Cardio- rebound sodium uptake after volume loss, hypertrophy
logy and the Canadian Cardiovascular Society [13,14] of the distal nephron and reduced tubular secretion all
consensus reiterate the immediate goals of hemodynamic contribute to diuretic resistance and predict a poor prog-
stabilization with weight reduction for the ADHF nosis [16,17]. Low-output states also impair renal per-
patient. Since no ideal drug currently exists a balanced fusion and prevent proper diuretic function. In these
therapeutic regimen including diuretics, vasodilators, and circumstances, changing the diuretic administration route
inotropes as well as ischemia and infection prevention is or combining diuretic therapy with inotropes, such as
the safest way of optimizing hemodynamics and coronary dobutamine or dopamine, to increase forward flow can be
perfusion in these patients. Refer to Fig. 1 for an over- efficacious. Other techniques to avoid diuretic resistance

Table 2 Classification of acute heart failure syndromes based on clinical presentation; adapted and modified [1]
Type of heart failure Clinical presentation

Acute decompensated
De-novo or as decompensated chronic heart failure Signs and symptoms of acute heart failure AND DO NOT fill criteria of cardiogenic
shock, pulmonary edema or hypertensive crisis
Pulmonary edema
Confirmed by physical exam and chest radiograph Respiratory distress, bilateral crackles, orthopnea, SpO2 090% on room air
Hypertensive acute heart failure
Preserved left-ventricular function and hypertension Sign and symptoms of acute heart failure, hypertension and pulmonary edema
confirmed by chest radiograph
High output failure
Arrhythmias, thyrotoxicosis, anemia, Paget’s disease Tachycardia, warm peripheries, pulmonary congestion
Can present with hypotension in septic shock
Cardiogenic shock
Tissue hypoperfusion induced heart failure despite Systolic blood pressure 90 mmHg or drop in mean arterial pressure
correction of preload 30 mmHg  low urine output (0.5 ml/kg/hr)
Pulse rate 60 beats/min  organ congestion
Right heart failure
Low-output syndrome Increased jugular venous pressure
Preload dependent Hepatic congestion
Hypotension

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 136 Heart failure

Figure 1 Immediate goals in treatment of the patients with acute heart failure [13]

ACEI, angiotensin-converting-enzyme
inhibitor; BNP, brain natriuretic peptide;
Acute heart failure with systolic dysfunction
CPAP, continuous positive airway
pressure; NTG, nitroglycerine; PDEI,
phosphodiesterase inhibitors; SBP, Oxygen/CPAP
systolic blood pressure. Furosemide + vasodilator
Clinical evaluation (leading to mechanistic therapy)

SBP >100 mmHg SBP 85--100 mmHg SBP <85 mmHg

Volume loading?
Vasodilator and/or inotropic inotrope
Vasodilator
(dobutamine, PDEI or levosimendan) and/or
(NTG, nitroprusside, BNP)
dopamine >5 µg/kg/min
and/or
norepinephrine

No response:
reconsider mechanistic therapy
Inotropic agents

Good response
Oral therapy
furosemide, ACEI

include fluid and sodium restriction, use of angiotensin- junction with furosemide, diuresis improved by at least
converting-enzyme inhibitors or combinations such as eight-fold in comparison to both agents alone. A1-receptors
loop and thiazides (Lasix infusion and metolazone or on myocardial cells also offer cardioprotective properties
hydrochlorothiazide) [17,18]. by activation of coronary artery vasodilation and inhibition
of norepinephrine and endothelin synthesis resulting in
There is evidence that low-dose furosemide in combi- less myocardial hypertrophy and remodeling [20,21].
nation with inotropes may enhance diuresis with less Ideally, research would lead to development of A1-recep-
adverse effects than high-dose boluses. A small random- tor antagonists with renal specificity to achieve diuresis
ized study comparing use of low-dose dopamine with without compromising long-term cardiac function.
different doses of furosemide showed that low-dose
dopamine with a low dose of furosemide (80 mg intra- More promising agents such as the vasopressin antagonist
venous twice daily) achieved adequate diuresis with Tolvaptan have shown significant improvements in
slight improvement in the creatinine clearance com- diuresis and weight loss in the acute setting. Arginine
pared with higher doses of furosemide (infusion of vasopressin is responsible for regulation of fluid balance,
10 mg/h). Overall, the data show that current diuretics vasoconstriction and myocardial remodeling. There are
improve symptoms from congestion with possible dele- two types of receptor, V1a and V2 receptors. V1a receptors
terious effects, such as impaired renal function and elec- activate peripheral arterial and coronary vasoconstriction,
trolyte abnormalities, at higher doses [18,19]. therefore increasing both preload and afterload. V2 recep-
tors are responsible for free water absorption in the renal
Novel natriuretic agents collecting duct by increasing the amount of aquaporin-2
Emerging therapies such as adenosine-receptor blockade within the membrane [10,22]. In acute heart failure, higher
may overcome the limitation of impaired glomerular levels of vasopressin, renin and norepinephrine circulate,
filtration. Renal A1-receptor blockade prevents arteriolar leading to suppressed myocardial and renal perfusion.
vasoconstriction and postglomerular vasodilation result- Also, plasma vasopressin (arginine vasopressin) levels
ing in improved glomerular blood flow [10,20]. A small are higher in acute and chronic heart failure patients than
randomized trial in New York Heart Association (NYHA) in normal individuals and levels are often elevated in the
Class III patients showed that an experimental form of absence of congestive symptoms. Although Tolvaptan, a
A1-receptor blockade, using BG-9719, was as capable of pure V2 antagonist, was developed, V1a blockade should
inducing natriuresis as furosemide while preserving base- theoretically improve hemodynamics by decreasing after-
line glomerular filtration rate. When administered in con- load and preventing ventricular remodeling [22,23].

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 Acute decompensated heart failure Gauthier et al. 137

Figure 2 Algorithm for acute heart failure treatment, data from Canadian Cardiovascular Society guidelines on the management of
acute decompensated heart failure [14]

AHF diagnosed, treatment initiated based on symptoms and signs

Volume overload +
Volume overload
low cardiac output

Moderate to severe
volume overload Very low output
Mild volume • inadequate response Mild to moderate • consider PA line
overload to IV diuretics low output • add vasodilator
• increased oxygen after BP stabilized
requirement
• CPAP and BiPAP
requirement
• fatigue

IV diuretics IV diuretics
IV furosemide bolus + IV vasodilators SBL >90 mmHg SBP <90 mmHg
• serum creatinine • consider • milrinone • dobutamine
<200 µmol/l 40 mg furosemide infusion 0.275 µg/kg/min or 2--5 µg/kg/min
• serum creatinine • add IV nitroglycerin • dobutamine • may also require
>200 µmol/l 80 mg starting at vasopressors
5--10 µg/kg/min
titrate to clinical status,
BP or PCWP, if available

AHF, acute heart failure; BiPAP, bilevel positive airway pressure; BP, blood pressure; CPAP, continuous positive airway pressure; IV, intravenous; PA,
pulmonary artery; PCWP, pulmonary capillary wedge pressure; SBP, systolic blood pressure.

The randomized trial EVEREST compared short and published data comparing high-dose nitrates with low-
long-term effects of Tolvaptan 30 mg/day with placebo dose furosemide and low-dose nitrates with high-dose
when added to standard therapy in ADHF with moderate furosemide in pulmonary edema demonstrated nitrate
to severe left-ventricular dysfunction. Weight reduction at effect peaked earlier, with more rapid relief of congestion
days 1 and 7 was significant after randomization but the and prevention of myocardial ischemia. Nitrates also
benefit in global clinical status was not sustained at 7 days reduced the need for mechanical ventilation with rapid
or discharge despite rapid resolution of symptoms [23]. reversal of pulmonary edema without significant hypo-
The long-term effects of oral Tolvaptan in the EVEREST tension [11,12,15,27].
outcome trial showed no reduction in long-term mortality
but significant improvement in secondary endpoints such Hydralazine is another potent peripheral arterial vaso-
as day-1 symptoms (dyspnea) and body-weight reduction dilator that is often used in conjunction with nitrates to
prior to discharge [24]. Also renal function was preserved achieve balanced arterial and venous dilation. The com-
and sodium improved in hyponatremic patients. Tolvap- bination of hydralazine and nitrates in the Al-HeFT
tan might become an attractive option for managing trial supported the theory that African-Americans have
congestion in ADHF patients once clinical benefit is decreased availability of nitric oxide, and in the setting
shown in different patient populations [25,26]. of hypertension have higher rates of hospitalization and
mortality when in acute heart failure [27–29]. Patients
Vasodilators receiving both hydralazine and nitrates had a 43%
Vasodilators such as nitrates decrease preload, and at reduction in all-cause mortality and a 33% reduction in
higher doses decrease afterload by causing smooth the rate of first hospitalization for ADHF when compared
muscle relaxation of the vascular wall [15]. Previously with placebo [30].

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 138 Heart failure

Natriuretic peptides are the last category of vasoactive with dobutamine. This class of inotrope is indicated in
drugs currently available in the US. Nesiritide, a recom- peripheral hypoperfusion and congestion refractory to
binant human brain natriuretic peptide, is a natural diuretics and vasodilators, with preserved systemic
endogenous hormone secreted by the ventricle in response blood pressure [41]. The OPTIME-CHF (Outcomes of
to wall stress and high diastolic volumes. These agents a Prospective Trial of Intravenous Milrinone for Exacer-
have both venous and arterial coronary vasodilatory bations of Chronic Heart Failure) group, the largest
properties, via increased production of cyclic GMP, result- randomized trial in the setting of hospitalized heart failure,
ing in smooth muscle relaxation without proarrhythmic studied hospitalization and mortality rate at 60 days in
effects [31–33]. The VMAC trial showed that Nesiritide NYHA class II or III patients with left-ventricular dysfunc-
provided similar symptomatic relief to nitroglycerine tion [42]. Milrinone was not associated with a reduction in
but a more rapid (3 h) and sustained (at least 24 h) either endpoint but had a tendency for higher mortality in
reduction in the pulmonary capillary wedge pressure comparison with placebo at 48 h (12.6 compared with 2.1%,
(
5.8 mmHg, P  0.001) when compared with standard P  0.001). It was also associated with high rates of adverse
care plus nitroglycerine (
3.8 mmHg, P  0.009) or events such as sustained hypotension [42].
placebo (
2.0 mmHg). Nesiritide also prevented myo-
cardial ischemia and had a similar safety profile and Dopamine, dobutamine and milrinone all improve con-
re-hospitalization rate to nitrates [34]. To study whether tractility by promoting cellular calcium influx thereby
Nesiritide can decrease the role of inotropes in ADHF it stimulating actin–myosin cross-bridging and myocyte
was compared with dobutamine and milrinone in small to shortening [42,43]. The ESCAPE trial published in
moderate nonrandomized trials. All showed mortality 2007 [41] revealed that inotropic agents such as dobuta-
and healthcare cost benefits with Nesiritide. Despite its mine and milrinone in heart-failure patients with low
rapid approval for the treatment of ADHF by the US Food ejection fraction and hypotension had higher 6-month
and Drug Administration, additional data from a small mortality rates [hazard ratio (HR) 2.14, 95% CI 1.10–
meta-analysis showed increased mortality and morbidity 4.15] than patients on vasodilators such as Nesiritide when
from renal failure [relative risk 1.54, 95% confidence compared with placebo (HR 1.39, 95% CI 0.64–3.0).
interval (CI) 1.19–1.98] [35,36]. Nesiritide continues to Inotropes in combination with vasodilators showed the
be used at this time but larger randomized trials are highest mortality (HR 2.90, 95% CI 1.88–4.48) [41].
ongoing to clarify its mortality benefit and adverse events
[37]. Despite associated morbidity and mortality, inotropes are
used in 10% of ADHF settings according to ADHERE
Inotropes data. Two novel therapies could dissociate inotropy
In ADHF, inotropes are commonly used in patients with from arrhythmogenicity: cardiac myosin activators and
persistent impaired hemodynamics. Unfortunately, their Istaroxime, a Naþ/Kþ-ATPase inhibitor. Both have
use is controversial due to potential harmful effects as shown promising results at the experimental animal level
they increase oxygen demand and intracellular calcium, [6,10].
thereby increasing myocardial ischemia and the risk of
progression to ventricular dysfunction and arrhythmias Calcium sensitizers are a new category of inotropes that
[31,38]. enhance myocardial performance by increasing the affinity
of troponin C to calcium. The prolonged, enhanced
Dobutamine is a synthetic sympathomimetic amine with contractility during systole (half-life of 80 h) does not
predominantly B1 and some B2-adrenergic effect pro- impair ventricular relaxation and is not cleared by the
ducing both dose-dependent inotropic and chronotropic kidneys [43–45]. Levosimendan is a member of this
response. At low doses, B2 stimulation is more significant pharmacological class that does not increase epinephrine
resulting in mild arterial vasodilatation and reduction of or norepinephrine concentrations, and so does not cause
after-load but at higher doses the inotropic and vasocon- vasoconstriction, remodeling or down-regulation of
striction effects are predominant. Different small trials cardiac receptor sensitivity. The LIDO study [46] looked
have demonstrated higher mortality rates in patients at hemodynamic improvement in cardiogenic shock.
receiving dobutamine or dopamine compared with placebo Levosimendan was clearly superior in reducing pulmonary
although the trend revealed improvement of NYHA class capillary wedge pressure (
7 compared with
3 mmHg,
in the inotrope group [39,40]. P  0.03) and long-term mortality at 6 months (26 com-
pared with 38%, P ¼ 0.029) when compared with dobuta-
Milrinone is a type of phosphodiesterase inhibitor which mine. The CASINO study [47], stopped early after interim
also has inotropic and vasodilatory effects with a more analysis, showed the superiority, in terms of combined
prominent effect on pulmonary vasculature. It can there- mortality and rehospitalization rates, of Levosimendan
fore cause a significant decline in pulmonary artery over both dobutamine and placebo (23.3, 40.1 and
pressure and pulmonary wedge pressure when compared 36.6% respectively, P ¼ 0.01) in ADHF [2,44,45]. The

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 Acute decompensated heart failure Gauthier et al. 139

two most recent trials, SURVIVE and REVIVE II, both is an effective and safe alternative therapy to fluid overload
support the symptomatic benefit of Levosimendan in in ADHF [55].
comparison with placebo. REVIVE II [48] showed a sig-
nificant global improvement of 33% at 5 days (P ¼ 0.015)
when compared with placebo, and shorter hospitalization Conclusion
in the Levosimendan group (7.0 compared with 8.9 days, ADHF remains a complex entity with therapeutic chal-
P ¼ 0.006). Although hypotension occurred more fre- lenges due to limited mortality data on current approved
quently in the Levosimendan group, mortality at 90 days and recommended pharmacological regimens. Intraven-
did not differ significantly between the two groups ous diuretics remain the mainstay of therapy in ADHF
(15.1 compared with 11.6%) [48]. SURVIVE [49,50] with congestive symptoms but the associated deleterious
showed no difference in 180-day mortality between Levo- effects support the combined use of diuretics and
simendan and dobutamine (26.1 compared with 27.9%, nitrates. Inotropes are sometimes necessary but again
HR 0.91, P ¼ 0.4). In a meta-analysis of LIDO, CASINO their associated mortality supports the need for innova-
and SURVIVE, mortality at 6 months was lower in the tive and safer agents.
Levosimendan group (relative risk 0.76, P ¼ 0.032) [51].
Despite Levosimendan’s approval in Europe as a second- Vasopressin antagonists could achieve adequate diuresis
line agent for severe low-output ADHF with or without without renal comprise while improving symptoms and
congestion refractory to standard therapy, or as a first-line weight reduction in congestive ADHF. Natriuretic
agent in cardiogenic shock, it is not part of the current peptides currently available in the USA could also
Canadian or North American recommendations. improve pulmonary congestion by potent vasodilation
and enhanced diuresis although recent mortality data
create ongoing controversy around this last class. Lastly,
Nonpharmacological therapies cardiac sensitizers approved in Europe offer an optimistic
Pharmacological therapy is the current standard of care for alternative to current inotropes for enhancing myocardial
the ADHF but nonpharmacological devices and assistance contractility without proarrhythmic effects.
can be beneficial. Respiratory therapies such as positive
pressure and mechanical ventilation should be an integral We can therefore be hopeful that future pharmacological
part of therapy in cardiogenic shock to maintain oxygen development will improve and simplify the management
saturation within the normal range to prevent end-organ of ADHF. These new discoveries may eventually help us
dysfunction, decrease diaphragmatic activity, and increase demystify this intricate condition.
functional residual capacity.

Small randomized trials have shown that continuous References and recommended reading
Papers of particular interest, published within the annual period of review, have
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