Download Pharmacotherapy for Acute Heart Failure Syndromes

Authors and Disclosures
James C. Coons, Pharm.D., BCPS, Molly McGraw, Pharm.D. and Srinivas Murali, M.D., FACC, FACP
James C. Coons, Pharm.D., BCPS (AQ Cardiology), is Clinical Specialist, Cardiology; and Molly Mcgraw, Pharm.D., is
Postgraduate Year 2 Critical Care Pharmacy Resident, Allegheny General Hospital, Pittsburgh, PA. Srinivas Murali,
M.D., FACC, FACP, is Professor of Medicine, College of Medicine, Drexel University, Philadelphia, PA, and Medical
Director, Gerald McGinnis Cardiovascular Institute, Allegheny General Hospital
Address correspondence to
Dr. Coons at the Department of Pharmacy, Allegheny General Hospital, 320 East North Avenue, Pittsburgh, PA 15212
([email protected]).
From American Journal of Health-System Pharmacy
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James C. Coons, Pharm.D., BCPS; Molly McGraw, Pharm.D.; Srinivas Murali, M.D., FACC, FACP
Posted: 01/11/2011; American Journal of Health-System Pharmacy. 2011;68(1):21-35. © 2011 American Society of HealthSystem Pharmacists, Inc.
Abstract and Introduction
Abstract
Purpose. Drug therapies for patients with acute heart failure syndromes (AHFS) are reviewed, including clinical
practice guideline recommendations for the treatment of hospitalized patients with heart failure (HF).
Summary. AHFS may be defined as new-onset, gradual, or rapidly worsening HF signs and symptoms that require
urgent therapy. Clinical practice guidelines from the American College of Cardiology Foundation–American Heart
Association, Heart Failure Society of America, and European Society of Cardiology offer recommendations for the
management of AHFS, addressing the role of diuretics, vasodilators, and inotropes. The guidelines emphasize the
utility of vasodilators for patients with signs and symptoms of pulmonary congestion, including pulmonary edema or
severe hypertension or both, who have not responded to diuretics. The early initiation of vasoactive medications,
including diuretics and vasodilators, has been linked to improved outcomes in some reports. Conversely, the use of
inotropes is deemphasized, particularly as part of the routine management of these patients. Newer agents, including
vasopressin antagonists, have also been approved recently but are not addressed by the clinical practice guidelines.
The guidelines address the importance of initiating and optimizing evidence-based oral medications for long-term use,
including angiotensin-converting-enzyme (ACE) inhibitors, angiotensin-receptor blockers, -blockers, and aldosterone
antagonists, during the patient's hospital stay in an effort to address long-term outcomes.
Conclusion. Drug therapy of AHFS may include diuretics, vasodilators, morphine, ACE inhibitors, digoxin, inotropes,
and vasopressin antagonists. Clinical practice guidelines for patients with AHFS provide a useful mechanism to
incorporate available evidence and standards of practice into patient care.
Introduction
At least 5 million people in the United States have heart failure (HF) and another 550,000 are diagnosed with HF each
year. The number of hospitalizations associated with HF as a primary diagnosis grew from 810,000 in 1990 to over 1
million in 1999 and from 2.4 million to 3.6 million for patients with a primary or secondary diagnosis of HF over the
same time period.[1] A retrospective cohort study of Medicare beneficiaries hospitalized with HF demonstrated that
short- and long-term outcomes from 2001 to 2005 continued to be poor and changed very little.[2] In fact, more than 1
in 10 patients died and more than 1 in 5 were readmitted within 30 days of hospitalization for HF. During a one-year
follow-up period, more than 1 in 3 patients died, and approximately two thirds were readmitted to the hospital. Even
more alarming is that 40% of patients were readmitted at least twice. The economic burden continues to be staggering,
with an estimated total cost of managing HF as a primary diagnosis in the United States of $39 billion in 2010.[3] While
these trends have occurred in the context of an aging population and better management of patients with acute
myocardial infarction (MI), it is clear that the management of HF continues to be a major public health challenge.
Several factors contribute to the difficulties in improving outcomes for patients hospitalized with HF, including the
heterogeneity of the patient population, high rate of co-morbid conditions, lack of a universally accepted definition for
acute HF, incomplete understanding of HF's pathophysiology, and general lack of evidence-based data for most HF
treatment regimens.[4] Clinical practice guidelines have recently been published to provide a better construct for
management of this patient population.[1,5,6] This review highlights guideline recommendations for the treatment of
hospitalized patients with HF and reviews the medical options for managing these patients.
Acute Heart Failure Syndromes
Acute heart failure syndromes (AHFS) may be defined as new-onset, gradual, or rapidly worsening HF signs and
symptoms that require urgent therapy.[7] Patients with AHFS can be further classified as having new-onset or
worsening chronic HF. Approximately 80% of patients with AHFS have chronic HF, whereas the remainder have newonset HF and may or may not have evidence of structural abnormalities (e.g., reduced ejection fraction).[4] Patients
with HF and a preserved left ventricular ejection fraction (LVEF) are just as likely to be hospitalized as those with a
reduced LVEF. Patients with advanced HF have low blood pressure (BP), renal impairment, and signs or symptoms
refractory to standard medical therapy and represent up to 10% of hospitalized patients with AHFS.[4]
The concept of AHFS as a patho-physiologic syndrome has been compared to acute coronary syndromes in that
patients have a spectrum of clinical profiles. Unlike acute coronary syndromes, in which the underlying
pathophysiology can be attributed to a unique precipitating event (e.g., plaque rupture with thrombosis), a common
process leading to AHFS has yet to be identified.[8] It is well established that there may be single or multiple underlying
etiologies of AHFS, including ischemia, hypertension, dysrhythmias, valvular abnormalities, renal insufficiency, and
iatrogenic effects. All of these factors may result in derangements in neurohormonal systems (e.g., renin–angiotensin–
aldosterone, sympathetic nervous system) and hemodynamics that ultimately affect the structure and function of the
myocardium.[7,8] Regardless of the underlying etiology, the most common presentation usually includes pulmonary and
systemic congestion without a reduction in cardiac output. Pulmonary congestion is defined by an increase in the left
ventricular filling pressure or preload and is reflected hemodynamically by an increase in the pulmonary capillary
wedge pressure (PCWP). A typical clinical manifestation is pulmonary edema with severe dyspnea, tachypnea,
tachycardia, and hypoxemia. Pulmonary congestion can be the result of an abrupt increase in BP, reflected as an
increase in vascular resistance or afterload and recorded hemodynamically as systemic vascular resistance (SVR).
Systemic congestion can result in jugular venous distention, peripheral edema, and increases in body weight. While
impaired cardiac output (CO) is less commonly seen in AHFS, it is characterized by tissue hypoperfusion with cool
extremities and the potential for end-organ damage (e.g., renal insufficiency).[4]
At least six clinical profiles that describe the hospitalized patient with HF have been proposed (Table 1).[4,6,7,9] This
classification addresses both clinical and etiologic factors, whereas another outlines clinical profiles based on the
degree of congestion and perfusion (Figure 1).[9,10] In fact, the latter has been shown to correlate with invasive
hemodynamics and provide prognostic information,[10] both of which are used to help guide therapeutic management.
Table 1. Clinical Classification of Acute Heart Failure Syndromes (AHFS)a
Clinical Profile
Comments
Therapeutic Interventions
Acute
decompensation of
History of progressive worsening chronic
HF, evidence of systemic and pulmonary
Loop diuretics, vasodilators
chronic HF
congestion
Acute HF with
hypertension or
hypertensive crisis
Systolic blood pressure of >160 mm Hg,
pulmonary congestion predominant,
systolic function generally preserved
Acute HF with
pulmonary edema
Abrupt onset with severe respiratory
distress, could be a result of acute
decompensation of chronic HF or of acute Loop diuretics, vasodilators, morphine
HF with hypertension or hypertensive
crisis
Acute coronary
15–25% of patients with ACS have HF
syndromes (ACS) and
signs and symptoms
AHFS
Loop diuretics, vasodilators
Reperfusion (e.g., percutaneous coronary
intervention, thrombolytics), antiplatelet
agents, anticoagulants, antiischemics
Cardiogenic shock
Often due to acute MI, organ
hypoperfusion despite adequate
correction of preload, oliguria or anuria
common
Inotropes, diuretics with or without
vasodilators, mechanical support (e.g.,
intraaortic balloon counterpulsation)
Isolated acute right
HF
May be due to pulmonary hypertension,
right ventricular infarct, pulmonary
embolus, valvular abnormalities; evidence
of systemic congestion with clear lungs
Nitrates, prostacyclins, endothelin
antagonists, or phosphodiesterase
inhibitors or any combination for select
patients; reperfusion for right ventricular MI
aAdapted
from references 4, 6, 7, and 9. HF = heart failure, MI = myocardial infarction.
Figure 1. Classification scheme for assigning clinical profiles in patients with advanced heart failure.9,10 Patients
may be classified as "warm" (indicating adequate perfusion) or "cold" (indicating compromised perfusion) by,
among other signs or symptoms, the hotness or coolness of their extremities. They may also be classified as
"wet" (indicating pulmonary congestion) or "dry" (indicating a lack of pulmonary congestion) by, among other
signs or symptoms, the presence of edema or rales. The profile labels (A, B, C, and L) are arbitrary.
Management
Approximately 80% of patients with AHFS receive initial care at the emergency department.[11] It is important in this
setting to define the clinical profile in order to evaluate the best approach to management. Another important first step
in evaluating patients hospitalized with HF is to identify the precipitating factor (Table 2). The recognition that
approximately 50% of readmissions after an index HF hospitalization are not related to HF underscores the
heterogeneity of AHFS and the need to promptly evaluate for potential etiologies.[4] Initial treatment goals for patients
are to improve symptoms, especially those that relate to pulmonary congestion or low cardiac output. Because
hospitalization for AHFS is one of the most important predictors of postdischarge mortality and readmission in patients
with chronic HF, goals to improve these outcomes should remain a top priority.[12,13] Other prognostic factors are
associated with greater postdischarge mortality and may help identify higher-risk patients and guide therapeutic
decision-making in AHFS. These factors include low systolic BP, coronary heart disease, troponin release, high blood
urea nitrogen (BUN), high serum creatinine (SCr) concentration, high BUN:SCr ratio, hyponatremia, increased levels of
natriuretic peptides, reduced PCWP during hospitalization, reduced functional capacity, and several other factors (e.g.,
nonuse of neurohormonal antagonists).[7]
Table 2. Precipitants of Hospital Admission for Heart Failurea
Precipitant
Examples
Indiscretion
Nonadherence with medications, restriction of sodium or fluids or both
Alcohol or illicit drug use
Iatrogenic factors
Negative inotrope use (e.g., verapamil, diltiazem, nifedipine, -blockers), class Ia and Ic
antiarrhythmics (e.g., procainamide, flecainide, propafenone)
Agents that promote retention of sodium or water or both (e.g., NSAIDs, corticosteroids,
thiazolidinediones, pregabalin)
Sympathomimetic use (e.g., pseudoephedrine, ephedra, amphetamines)
Cardiotoxins (e.g., anthracyclines, trastuzumab, alcohol, cocaine)
Dysrhythmias
Atrial fibrillation, atrial flutter
Hypertension
Uncorrected high blood pressure
Ischemia
Acute coronary syndromes
Valvular disorders Mitral regurgitation
Endocrine
disorders
Diabetes mellitus, hyperthyroidism, hypothyroidism
Hematologic
disorders
Anemia (e.g., bleeding, bone marrow suppression)
Infection
Pneumonia, viral illness
Pulmonary
disorders
Pulmonary embolus, chronic obstructive pulmonary disease
Renal disorders
Renal failure, cardiorenal syndromes
aAdapted
from references 1 and 5. NSAIDs = nonsteroidal antiinflammatory drugs.
Overview of Guidelines
Clinical practice guidelines for the management of AHFS have only recently been addressed.[1,5,6] Guidelines
addressing this patient population have been promulgated by the Heart Failure Society of America (HFSA), the
American College of Cardiology Foundation/American Heart Association (ACCF/AHA), and the European Society of
Cardiology (ESC). The lack of evidence-based guidelines to this point is largely reflective of the relative paucity of
robust data.[1] In fact, the first randomized trial of therapies for AHFS was published in 2002.[14] Further, no placebocontrolled trial of pharmacotherapy for AHFS has shown an improvement in short-term survival or hospital
readmissions.[7] Published studies to date have generally focused on symptomatic relief and hemodynamic
improvement. Nonetheless, guidelines provide a useful construct for bridging the gap between evolving evidence and
current practices. Guideline recommendations from professional organizations are based on randomized trials, large
registries, and expert opinion. Pharmacotherapeutic recommendations are generally congruent, with each group
addressing the role of diuretics, vasodilators, and inotropes. A consistent theme is the increased emphasis on the utility
of vasodilators for patients with signs and symptoms of pulmonary congestion, including pulmonary edema or severe
hypertension or both, that have not responded appropriately to diuretics. Conversely, the use of inotropes is deemphasized, particularly as part of the routine management of these patients. Inotropes are best reserved to
ameliorate symptoms and improve end-organ function in the setting of advanced HF (e.g., systolic BP of <90 mm Hg
despite adequate left ventricular filling pressures, not responsive to other therapies).[1,5,6] A comparison of the
guidelines is presented in the appendix.
Pharmacotherapeutic Options
While the clinical practice guidelines are integral to developing a uniform approach to the pharmacologic management
of AHFS, observational data from large registries also serve a practical purpose to understanding and analyzing
current treatment patterns. The Acute Decompensated Heart Failure National Registry (ADHERE) database is one
such observational database that collected data across the spectrum of the patient's hospital course with HF.[15] Data
from this registry have been extensively analyzed and provide a perspective on real-world treatment and inhospital
clinical outcomes. For example, it has been estimated that 88% of patients with HF received i.v. loop diuretics during
their hospitalization.[11] Only about 18% of patients received i.v. vasodilators, including nitroglycerin and nesiritide,
during their hospitalization. Interestingly, sodium nitroprusside represented <1% of all vasodilators used.[16] These are
notable findings, given that up to two thirds of patients with AHFS have a clinical picture consistent with hypertensive
crisis with an increase in SVR.[17] This scenario leads to a worsening of diastolic or systolic function or both through
increased myocardial wall stress and a resultant reduction in CO along with volume overload. Consequently, diuretics
and vasodilators are the mainstays of treatment for addressing this clinical picture and are the focus of the clinical
practice guidelines.
Diuretics
All three of the clinical practice guidelines advocate i.v. loop diuretics as the preferred first-line therapy for patients with
evidence of volume overload. ACCF/AHA guidelines advise the initiation of these drugs in either the emergency
department or clinic setting.[1] The early initiation of vasoactive medications, including diuretics, has been linked to
improved outcomes in recent reports.[17–19] Diuretics have gained widespread acceptance in the management of HF,
despite limited formal evaluation in randomized clinical trials.[20] Diuretics are known to improve symptoms of
pulmonary congestion and decrease body weight; however, these short-term clinical benefits have not shown
improvements in rehospitalization or mortality.[4,21] Furosemide, bumetanide, and torsemide are the most commonly
used diuretics and demonstrate some important pharma-cokinetic differences. Furosemide is primarily eliminated
renally, whereas bumetanide and torsemide are hepatically metabolized. Consequently, longer half-lives may be
observed with different agents in the setting of renal or hepatic disease. The oral bio-availability of furosemide is erratic
and less predictable compared with the relatively complete absorption of bumetanide and torsemide.[22] Other potential
differences in neurohormonal activity have been described in animal models, with torsemide, as opposed to
furosemide, having an inhibitory effect on aldosterone activity.[23] Nonetheless, all three of the commonly prescribed
loop diuretics are a mainstay in the management of AHFS.
Despite the well-established, short-term benefits of loop diuretics, several observational studies have shown an
association among these medications and the risk for rehospitalization or death from worsening HF, increased length
of stay, and higher resource utilization.[21,24,25] Reasons for this are not completely clear but may relate to
augmentation of neurohormonal pathways, including the renin–angiotensin–aldosterone system due to reductions in
intravascular volume and sodium depletion. In accordance with these findings is the observation that diuretics are
known to adversely affect renal function, which is an independent predictor of mortality in patients with HF.[1,16,26] The
dose–response relationship with i.v. diuretics has also been long debated, and recommendations have largely been
empirical. The ACCF/AHA guidelines recommend an initial i.v. dose that equals or exceeds the patient's long-term oral
daily dose. Dosage should be adjusted to attain symptom relief while avoiding a rapid reduction in intravascular
volume. Recent studies have provided some clarity to the dose–response debate. An analysis of the Evaluation Study
of Congestive Heart Failure and Pulmonary Artery Catheter Effectiveness (ESCAPE) trial database showed a dosedependent relationship with mortality risk, especially with a furosemide dosage exceeding 300 mg/day.[27] A singlecenter study also demonstrated a dose-dependent mortality effect with diuretics.[28] The highest quartile of the daily
diuretic dose (>160 mg furosemide or equivalent) had the highest risk-adjusted mortality rate. The association between
loop diuretic use and worse outcomes at higher doses must be tempered by the fact that data supporting this link are
observational in nature. It is often difficult to control for numerous clinical variables that increase patients' risk for worse
outcomes (e.g., advanced HF, renal insufficiency, multiple co-morbidities) and result in the need for higher doses of
diuretics.
One of the major challenges encountered with i.v. loop diuretics is how to care for patients who have not responded to
initial doses, as evidenced by continued volume overload. Both the ACCF/AHA and HFSA guidelines present three
treatment options for these patients: increase the dosage of the loop diuretic, add a second type of diuretic (e.g.,
metolazone), or switch to a continuous infusion of a loop diuretic.[1,5] Potential pharmacodynamic advantages to using
a continuous infusion include a more constant delivery of medication to the renal tubule, thus avoiding fluctuations in
serum levels. Higher levels may be associated with ototoxicity, whereas lower levels may lead to rebound sodium
reabsorption.[29] A Cochrane review evaluating eight trials found greater urine output and less ototoxicity with
continuous infusions compared with intermittent bolus injections of diuretics.[30]
Results from the Diuretic Optimization Strategies Evaluation in Acute Heart Failure (DOSE) study were recently
presented.[31] The objective of the study was to better understand the potential negative implications of high-dose
diuretics as well as the optimal dosage and duration. Approximately 300 patients with chronic HF receiving oral daily
doses of loop diuretics (furosemide 80–240 mg or equivalent) were randomized to i.v. treatment in a 2 × 2 factorial
design (every 12 hours i.v. bolus versus continuous i.v. infusion, plus low intensification to a daily i.v. dose equivalent
to the oral dose versus high intensification to a daily i.v. dose 2.5 times the oral dose of furosemide). It is important to
point out that patients who required i.v. vasodilators or inotropes or who had a SCr concentration of <3 mg/dL were
excluded. The main efficacy endpoint was patient global assessment of symptom relief as assessed by visual
analogue scale area under the curve over 72 hours. Change in SCr level was the primary safety endpoint. Overall,
neither global symptom relief nor change in SCr concentration was significantly different in either comparison of
administration technique or dose. Furthermore, continuous infusion dosing was not associated with improvements in
any of the secondary endpoints, including net diuresis, change in weight, and treatment failure. Dose intensification,
however, did improve the aforementioned secondary endpoints. One of the limitations of this trial was that medical
therapy for HF could be adjusted based on clinical response 48 hours after randomization. Therefore, evaluation of the
48-hour endpoint may provide more insight into potential differences.
Vasodilators
When managing patients in the early phase of AHFS, the key goals of management include hemodynamic stabilization
and symptom improvement. The vasodilators have been shown to meet both needs by reducing preload, afterload, or
both. The agents decrease BP, PCWP, and SVR to reduce dyspnea and improve peripheral oxygen delivery. The
efficacy of high-dose nitroglycerin in this setting is demonstrated by prompt resolution of symptoms, including
decreased pulmonary congestion, decreased need for mechanical ventilation, and a reduction in intensive care unit
(ICU) admission.[18] Similar to the beneficial role of nitroglycerin, data regarding the early initiation of nesiritide in
patients with AHFS have shown positive results.[17] Observations from the ADHERE registry showed increased overall
survival with the use of nitroglycerin or nesiritide compared with inotropic therapy with dobutamine or milrinone;
however, it is possible that patients requiring inotropic therapy had a more-advanced form of HF than did those
receiving vasodilators.[16] Although clinical trial evidence is limited, recommendations addressing the role of
vasodilators in patients with AHFS are provided. HFSA and ACCF/AHA guidelines recommend considering
nitroglycerin, sodium nitroprusside, or nesiritide as an adjunct to diuretics for rapid resolution of congestive symptoms
in the normotensive or hypertensive patient.[1,5] Likewise, ESC guidelines recommend i.v. nitrates or sodium
nitroprusside at an early stage for AHFS patients with a systolic BP of >90 mm Hg and without serious obstructive
valvular disease.[6]
Nitroglycerin
Nitroglycerin is an organic nitrate that exerts its pharmacologic actions through nitric-oxide-mediated smooth muscle
vasodilation. It produces venous vasodilation at lower doses and, as the rate is increased, arterial vasodilation may
also occur. Nitroglycerin reduces preload (PCWP, central venous pressure) and arterial BP. Nitroglycerin is an
effective therapy to assist with the management of patients with AHFS by ultimately decreasing cardiac filling
pressures and increasing CO. In the setting of AHFS, nitroglycerin is best used in a patient who fits a clinical profile
displaying volume overload with a normal to elevated BP and a lack of response to i.v. diuretic therapy. Nitroglycerin is
also preferred in the setting of acute coronary syndromes and AHFS due to coronary vasodilation. The hemodynamic
responses to i.v. nitroglycerin are rapid and short acting, which allows for frequent dose escalation. Dosing and
monitoring recommendations for nitroglycerin and other vasodilators are provided in Table 3. The usual dosage
required varies significantly by patient but generally should not be increased beyond 200 μg/min. Patients who do not
achieve hemodynamic improvement with a dosage of approximately 200 μg/min can be considered nonresponders.[5]
Tachyphylaxis can occur in patients receiving continuous-infusion nitroglycerin for greater than 24 hours but may be
apparent more quickly in patients receiving higher dosages. Potential adverse effects associated with nitroglycerin
include headache, hypotension, abdominal discomfort, reflex tachycardia, and paradoxical bradycardia.
Table 3. Dosing of I.V. Vasodilators and Inotropesa
Medication
Initial Dosage
Typical Dosage
Range
Adjustment Increment
Nitroglycerin
10 g/min
5–200 g/min
10–20 g/min every 5–15 min
Sodium nitroprusside
0.2 g/kg/min
0.5–5 g/kg/min
0.25–0.5 g/kg/min every 5–15 min
Nesiritide
Loading dose: 2
ìg/kgb
Infusion: 0.01
g/kg/min
0.01–0.03
g/kg/min
0.005 g/kg/min; bolus: 1 g/kg every 3 hr to
maximum dose
Dobutamine
hydrochloridec
2.5–5 g/kg/min
2.5–20 g/kg/min
2.5–5 g/kg/min every 5–15 min
Milrinone lactatec
Loading dose: 50
g/kgb
Infusion: 0.25
g/kg/min
0.25–0.75
g/kg/min
Adjustment usually not recommended
aAdapted
from references 6, 32, and 36.
bMay
omit loading dose if there is a concern for hypotension.
expressed in terms of the base.
cDosage
Although clinical trial data evaluating the efficacy of nitroglycerin are minimal, the drug remains a cornerstone of
therapy for patients with ischemic heart disease and AHFS. One randomized trial conducted in patients with earlyphase AHFS compared the effects of two different treatment regimens: nitrates and diuretics.[20] One group of patients
received high-dose furosemide with low-dose isosorbide dinitrate, and the comparator group used high-dose
isosorbide dinitrate with low-dose furosemide. The main goal of treatment was to rapidly reduce pulmonary edema
without compromising BP. The main outcome measures evaluated were inhospital death, need for mechanical
ventilation within 12 hours of admission, and development of MI within 24 hours of admission. While relief of pulmonary
congestive symptoms was accomplished in both treatment groups, the effect of high-dose nitrate therapy was superior
in terms of need for mechanical ventilation and development of MI. However, there was no significant difference
between the two treatment groups in the rate of inhospital death.
Sodium Nitroprusside
Sodium nitroprusside is a potent, direct-acting vasodilator with a similar mechanism of action to nitroglycerin. However,
sodium nitroprusside provides rapid and pronounced venous and arterial vasodilation at usual dosages. The reductions
in preload, afterload, and arterial BP make it particularly useful for patients with AHFS and advanced HF. CO also can
increase to near-normal levels because of the effects on cardiac filling pressures.[5,32,33] In most institutions, the use of
sodium nitroprusside requires invasive monitoring of BP and central hemodynamics. Sodium nitroprusside dosages
can be adjusted rapidly until hemodynamic goals are met, and SVR can be used to help guide dosing. However, slow
weaning to discontinuation is advised because of the potential for rebound vasoconstriction.[5]
Sodium nitroprusside is converted to both nitric oxide and cyanide and initially cleared through nonenzymatic
mechanisms. The liver converts cyanide to thiocyanate, whereas the kidneys eliminate thiocyanate.[33] One of the main
concerns of using sodium nitroprusside is the risk of cyanide and thiocyanate toxicities, especially in patients who have
hepatic or renal insufficiency or patients maintained on sodium nitroprusside 3 μg/kg/min for more than 72 hours.[32]
While the risk of toxicity in patients with AHFS is rare when lower dosages are used, health care providers should be
cognizant of the development of its signs and symptoms. The presentation of cyanide toxicity may include mental
status changes (e.g., confusion, psychosis), muscle spasm, convulsions, cardiovascular instability, or unexplained
metabolic or lactic acidosis. Thiocyanate toxicity can present in a similar fashion, along with other nonspecific
symptoms such as nausea, vomiting, tinnitus, and fatigue.[32,33] Like other i.v. vasodilators, sodium nitroprusside can
also produce hypotension in some patients. Consequently, the absence of systemic hypotension is paramount before
the initiation of therapy for AHFS.[1,5,6] Lastly, sodium nitroprusside is not recommended for patients with ischemia due
to the risk of the coronary steal phenomenon, in which blood is shunted away from ischemic areas to small resistance
vessels.[32,33]
Similar to the other agents in this class, clinical trial data evaluating the efficacy of sodium nitroprusside are limited.
However, the drug does appear to serve a role in patients with AHFS and evidence of increased afterload and
decreased CO. One retrospective study evaluating the safety and efficacy of sodium nitroprusside in patients with
AHFS and a low CO found that patients treated with sodium nitroprusside achieved greater improvement in cardiac
index (CI), significantly lower all-cause mortality, and fewer clinical adverse effects at long-term follow-up than did
patients not receiving sodium nitroprusside.[34] One limitation of this study was its nonrandomized design, which may
have introduced selection bias. The majority of patients selected to receive sodium nitroprusside tended to have higher
BP and lower CO, the population that would benefit most from the use of a vasodilator. Another single-center study
evaluating the role of sodium nitroprusside in patients with severe aortic stenosis and left ventricular dysfunction
concluded that the drug rapidly and significantly improved the CI from a baseline mean of 1.6 to 2.22 L/min/m2 at 6
hours, along with a further increase to 2.52 L/min/m2 at 24 hours.[35] The investigators concluded that sodium
nitroprusside is a valid option for optimizing cardiac function before aortic valve replacement in patients with left
ventricular failure or for converting to an oral vasodilator regimen in patients not undergoing surgery.
Nesiritide
Nesiritide, or recombinant human brain-type natriuretic peptide (BNP), is labeled for the treatment of patients with
acute de-compensated HF who have dyspnea at rest or with minimal physical activity.[36] BNP is an endogenous
hormone produced in the ventricular myocardium in response to increased wall stress, hypertrophy, and volume
overload. The hemodynamic effects of BNP include arterial and venous vasodilation, natriuresis, diuresis, and
attenuation of the renin– angiotensin–aldosterone and sympathetic nervous systems.[37] Nesiritide has been shown to
reduce PCWP, pulmonary vascular resistance, and mean and systolic pulmonary artery pressures and significantly
improve CO compared with nitroglycerin and placebo.[38] One potential advantage of using nesiritide is its ability to
rapidly reduce hemodynamic markers, especially PCWP, by achieving 90% of its peak effect within 30 minutes.[36]
Nesiritide is generally infused for a total duration of 72 hours or less, and, in the largest clinical trial to date, the median
duration of use was 24 hours.[38] Because nesiritide has a longer half-life (median of 20 minutes) than the previously
discussed vasodilators, adverse effects such as hypotension can persist for a significantly longer period of time. If
symptomatic hypotension occurs, the infusion should be discontinued until resolution of symptoms and until the systolic
BP is greater than 90 mm Hg.[36] Once BP is corrected, nesiritide may be restarted at a 30% lower infusion rate without
a bolus dose. Conservative dosing by omitting the initial bolus dose has been proposed as a means of minimizing
hypotension.[1] The package insert information states that nesiritide should not be used in patients with a systolic BP of
<90 mm Hg.[36] In addition, nesiritide should not be used as first-line treatment for patients in cardiogenic shock.
The Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) trial was the largest prospective
randomized trial of patients with AHFS conducted to date.[38] This study randomized 489 patients to receive nesiritide,
nitroglycerin, or placebo for 24 hours. The primary endpoints of the study were change in PCWP and dyspnea
improvement at 3 hours. Results of this trial found the difference in PCWP (from baseline to 3 hours) between
nesiritide and nitroglycerin to be statistically significant, with a mean reduction of 5.8 mm Hg versus 3.8 mm Hg,
respectively (p = 0.03). However, the nitroglycerin doses used were relatively small and could account for some of the
differences observed. Patients' self-assessment of dyspnea at 3 hours was similar with nesiritide and nitroglycerin but
significantly improved compared to placebo (p = 0.03).
Since the marketing approval of nesiritide in 2001, controversy has existed as to whether its use is beneficial for
preserving or improving renal function. The evidence to support these effects are conflicting.[39,40] In addition, metaanalyses found that treatment with nesiritide may be associated with worsening of renal function and short-term
mortality.[41,42] Since the publication of these studies, there has been a dramatic decline in the use of nesiritide in
clinical practice.[43] An expert panel committee has since convened to review all available data surrounding the safety
of nesiritide in response to publication of the aforementioned meta-analyses.[44] The committee did note a dosedependent increase in SCr levels, indicating renal dysfunction, at dosages within the normal range. The panel also
noted that completed trials have shown a trend toward increased mortality at 30 days, but not at 180 days, with the use
of nesiritide. The overall findings of the meta-analyses remain inconclusive due to the varying methodologies and
patient characteristics within each of the studies included. In summary, the expert panel reiterated that nesiritide should
not be used to replace or enhance diuretics or to improve renal function. Nesiritide also should not be used for
scheduled repetitive or intermittent outpatient use. Data from the Second Follow-Up Serial Infusions of Nesiritide
(FUSION II) trial underscored this recommendation, as there was no benefit with nesiritide in outpatients at high risk for
decompensation.[45] Likewise, the use of nesiritide in an emergency department or observation unit did not improve
outcomes, including the need for hospitalization.[46]
The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) will further
evaluate the efficacy and safety of nesiritide and will be the largest trial ever conducted for AHFS.[47] In this
randomized, double-blind, placebo-controlled, multicenter trial, approximately 7000 patients with AHFS will be
randomized to receive nesiritide or placebo for a minimum of 24 hours and up to seven days. This study is designed to
assess whether nesiritide plus standard care compared with placebo and standard care will provide significant
improvements in symptoms, HF rehospitalizations, and mortality after admission to the hospital. Other specific
endpoints to be addressed in this study include renal function and overall safety.
Morphine
The role of morphine in the setting of AHFS is uncertain. Morphine's use in the early stabilization of patients with AHFS
has been accepted for many years based on its hemodynamic and sedative properties. Morphine has been reported to
reduce preload, heart rate, and possibly afterload, the net effect of which is a reduction in myocardial oxygen demand.
Evidence supporting its use is very limited despite its widespread application.[6] A recent observational analysis from
the ADHERE registry suggested that the use of morphine is associated with worse outcomes in AHFS, including the
need for mechanical ventilation, a longer length of stay, a higher ICU admission rate, and a higher overall risk-adjusted
mortality.[48] Although HFSA guidelines do not provide a formal recommendation for the use of morphine, they do state
that it should be used with caution, especially in patients with altered mental status and impaired respiratory drive.[5]
ESC guidelines state that morphine should be considered for patients with severe symptoms of AHFS plus
restlessness, dyspnea, anxiety, or chest pain.[6] I.V. bolus doses of morphine sulfate (2.5–5 mg) can be considered and
repeated as necessary; however, careful attention must be made to monitoring of respiratory status. Caution must also
be exercised when using morphine in patients with hypotension, bradycardia, advanced atrio-ventricular block, or
carbon dioxide retention. Nausea is a well-known adverse effect of morphine and may require treatment with an
antiemetic.[6] ACCF/AHA guidelines do not address morphine use for AHFS.
Angiotensin-converting-enzyme Inhibitors
Angiotensin-converting-enzyme (ACE) inhibitors do not have a clear role in the early management of AHFS, as
randomized, controlled trial data are lacking. However, ACE inhibitors may be considered in the setting of acute
coronary syndromes with evidence of left ventricular dysfunction and HF.[6] Caution is warranted in patients with a
marginal BP, and i.v. ACE inhibitors in particular should be avoided in such patients.[49] ESC guidelines do not endorse
the early use of ACE inhibitors, though the American College of Emergency Physicians advises that they may be used
based on favorable hemodynamic effects (decreased preload and afterload). Vigilant monitoring for first-dose
hypotension is needed.[50] ACCF/AHA and HFSA guidelines do not address the early use of ACE inhibitors for AHFS.
The role of oral ACE inhibitors for chronic HF is well established.
Digoxin
Digoxin has beneficial neurohormonal and hemodynamic effects in the setting of HF, including vagomimetic effects,
attenuation of the renin–angiotensin–aldosterone system, reduced PCWP and SVR, increased CO, and improved
LVEF.[51] Accordingly, digoxin has been viewed as a favorable therapeutic alternative for the management of AHFS,
even though studies examining clinical outcomes have yet to be conducted.[52] ESC guidelines briefly discuss the role
of digoxin for AHFS in the context of its modest inotropic effects, ability to reduce filling pressure, and ability to
decrease ventricular rate in patients with atrial fibrillation (class IIb, level C recommendation).[6] Digoxin is not
addressed in either ACCF/AHA or HFSA guidelines for AHFS.
Inotropes
Inotropes may be considered for hospitalized patients with AHFS and low output syndrome. Dobutamine or milrinone,
in particular, may be considered for relief of symptoms and to improve end-organ function in patients with severe
systolic dysfunction. Inotropes may also be of value in patients who have marginal systolic BP or symptomatic
hypotension and are intolerant to vasodilators due to hypotension and in patients who have not adequately responded
to vasodilator therapy.[53] Data from the ADHERE registry illustrate that out of greater than 150,000 patients, fewer than
3% had a systolic BP of <90 mm Hg, and approximately 50% had a preserved systolic function.[15] However,
approximately 14% of the patients in ADHERE were treated with an i.v. inotropic agent. These patients had a higher
mortality rate (19%) than all other non-inodilator-treated patients (14%).[16] The HFSA, ACCF/AHA, and ESC all deemphasize the role of inotropes compared with vasodilators for adjunctive management of AHFS due to a lack of
controlled studies establishing a clear benefit and the adverse-event risk profile including arrhythmias, hypotension,
and myocardial ischemia. Current guidelines suggest the use of inotropic agents for symptom relief and end-organ
function improvement in patients with low systolic BP (<90 mm Hg) and evidence of low output.[1,5,6] Some patients
may continue to require an inotrope to maintain sufficient CO beyond their hospitalization. In these cases, inotropes
are also used as a "bridge" to more definitive or destination therapy, including cardiac transplantation, mechanical
circulatory support (ventricular assist device), or revascularization. For patients who are not candidates for these
options and have end-stage HF, inotropes may be offered for palliation of symptoms.[5]
Dobutamine
Dobutamine is a synthetic catecholamine that has both inotropic and vasodilatory effects. Its mode of action is
mediated via stimulation of both 1- and 2-adrenergic receptors. By working on these receptors, it produces a dosedependent increase in CO and a decrease in PCWP. A reduction in SVR may be seen secondary to its effects at the
[54] The favorable inotropic and vasodilatory effects of dobutamine make it a preferred agent for the
2-receptor
management of patients with AHFS and low output syndrome. Dobutamine begins to work within 1–2 minutes but may
take up to 10 minutes to exert its peak effect. Tachyphylaxis may occur in patients using dobutamine for greater than
24–72 hours; therefore, upward dosage adjustment may be needed in patients when a decline in CO is noted. Notable
adverse effects of dobutamine include hypotension and tachyarrhythmias (e.g., atrial fibrillation, ventricular
tachycardia). Long-term use of dobutamine has been associated with decreased survival, mainly attributable to sudden
cardiac death.[55]
The Prospective Randomized Evaluation of Cardiac Ectopy with Dobutamine or Natrecor Therapy (PRECEDENT) was
a multicenter, randomized, open-label, active-control trial designed to compare the safety of dobutamine at a dosage of
at least 5 μg (as the hydrochloride salt)/kg/min and two fixed doses of nesiritide (0.015 and 0.030 μg/kg/min, with no
bolus dose) for their effects on heart rate and ventricular arrhythmias in patients with AHFS.[56] Results of this study
found that dobutamine significantly increased all measures of ventricular ectopy. In addition, nesiritide reduced the
frequency of ventricular tachycardia at 24 hours. With regard to improvement of signs and symptoms of congestive HF,
both drugs were comparable. Although additional studies evaluating the efficacy of dobutamine in patients with AHFS
are lacking, it remains a first-line option for patients with marginal BP and reduced CO requiring inotropic support.
Milrinone
Milrinone is a phosphodiesterase (PDE) type-3 inhibitor that has similar effects to dobutamine. PDE type 3 is an
enzyme that breaks down intracellular cyclic adenosine monophosphate (cAMP) to its inactive metabolite.[53] Inhibition
of this conversion allows for increased intracellular calcium concentration and contractility and myocardial relaxation.
An increased cAMP in the periphery produces arterial and venous vasodilation, leading to decreased systemic and
pulmonary vascular resistance, decreased left and right filling pressure, and increased CO.[53] In contrast to other
catecholamines, milrinone exerts its effects without stimulating -adrenergic receptors; subsequently, tachyphylaxis
due to downregulation of -receptors is not a concern. Milrinone has also been shown to have a greater vasodilatory
effect than dobutamine, as demonstrated by further reductions in key hemodynamic markers (pulmonary artery
pressures, PCWP, and SVR). Conversely, dobutamine may have a greater degree of effect on CO than milrinone but
at the expense of greater increases in heart rate and myocardial oxygen consumption.[55] The adverse-effect profile of
milrinone is an extension of its hemodynamic effects. Hypotension is of greater concern with milrinone due to its
vasodilatory effects, which can be compounded by its prolonged half-life (one to three hours) and renal elimination.[54]
Consequently, dosing strategies typically omit the initial bolus dose and advise against dosage adjustment. In fact,
bolus-free dosing has been shown to provide significant hemodynamic changes within 30 minutes and becomes similar
to bolus dosing by three hours.[57] Similar to dobutamine, milrinone can potentiate atrial or ventricular arrhythmias, and
long-term use is associated with decreased survival due to sudden cardiac death.[55]
The use of milrinone in AHFS has been evaluated in limited randomized controlled trials. The largest trial of these is
the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIMECHF), which assessed the effects of short-term use of milrinone in addition to standard therapy.[14] The primary efficacy
endpoint was the total number of days hospitalized for cardiovacsular causes within 60 days after randomization. The
main secondary endpoint included the proportion of cases failing therapy because of adverse events or worsening HF
48 hours after initiating therapy. The results of this trial concluded that the use of milrinone for patients with AHFS did
not significantly decrease days of hospitalization compared with placebo. Furthermore, use of milrinone resulted in a
significant increase in adverse events related to sustained hypotension and atrial arrhythmias. Consequently, the
authors concluded that the routine use of milrinone in AHFS is not supported.[14] Comparisons with dobutamine are
sparse, but one retrospective analysis demonstrated no difference in clinical outcomes.[58] Dobutamine may be an
initial choice over milrinone in patients with severe renal dysfunction to lessen the potential for adverse effects (e.g.,
hypotension) with drug accumulation. Milrinone, however, would be preferred as maintenance therapy with -blockade,
as it retains its hemodynamic effects by acting on post- -receptor mechanisms.[59] Finally, milrinone may be
considered as first-line therapy over dobutamine for patients with AHFS and evidence of severe pulmonary
hypertension due to more-pronounced vasodilatory properties.[58]
Vasopressin Antagonists
Vasopressin concentrations are known to be elevated in HF, correlate with its severity, and contribute to both fluid
retention and hyponatremia.[60] In addition, hyponatremia is a known predictor of mortality in patients hospitalized with
HF.[61] As a mediator of ongoing neurohormonal activation in HF, vasopressin has become a pharmacotherapeutic
target of interest. Antagonism of V1A receptors located in the systemic vasculature results in vasodilation, whereas
inhibiting the V2 receptors in the kidneys leads to an increase in free water clearance (aquaresis) and serum sodium
level and a decrease in urine osmolality. The currently available vasopressin antagonists include conivaptan and
tolvaptan. Conivaptan is a dual V1A/V2-receptor antagonist given via the i.v. route, whereas tolvaptan is a selective V2receptor antagonist given orally. Both agents are labeled for hypervolemic and euvolemic hyponatremia; however, only
tolvaptan is labeled for patients with HF in either of these settings. Key monitoring values for these agents include
serum sodium levels in the hospital setting due to the potential for overly rapid correction of sodium (>12 meq/L/day)
resulting in osmotic demyelination syndrome. Common adverse effects include thirst, dry mouth, and (for conivaptan)
infusion-site reactions. Both agents are extensively metabolized by the cytochrome P-450 isoenzyme system;
therefore, strong inhibitors and inducers of this pathway should generally be avoided.[62,63]
HFSA guidelines recommend water restriction and optimization of ACE inhibitors or angiotensin receptor blockers for
the treatment of hyponatremia.[5] For refractory hyponatremia, the guidelines advise seeking alternative causes (e.g.,
hypothyroidism, hypoaldosteronism, syndrome of inappropriate antidiuretic hormone). HFSA does acknowledge
vasopressin antagonists as being effective at increasing serum sodium and state that it may be reasonable to add a
nonselective vasopressin antagonist to treat patients with significant cognitive symptoms in the setting of
hyponatremia. However, the guidelines provide no clear role for this class and reinforce that long-term therapy does
not improve outcomes. The largest-scale trial to date of vasopressin antagonists was the Efficacy of Vasopressin
Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST).[64] In EVEREST, no differences were found
in terms of all-cause mortality, cardiovascular death, or hospitalizations for HF with tolvaptan in addition to standard
therapies versus placebo among 4133 patients. Neither the ACCF/AHA nor the ESC guidelines provide any
recommendations regarding the use of vasopressin antagonists.[1,6]
Special Considerations in AHFS Management
BNP-guided Pharmacotherapy
Current guidelines acknowledge the value of BNP or N-terminal proBNP (NT-proBNP) for both diagnostic and
prognostic purposes.[1,5,6] Consequently, there has been increasing interest in using natriuretic peptide levels to guide
pharmacotherapy and improve outcomes for patients with HF. The Trial of Intensified vs. Standard Medical Therapy in
Elderly Patients with Congestive Heart Failure (TIME-CHF) compared 18-month survival free of any hospitalization and
quality of life among 622 patients with chronic HF randomized to either intensified NT-proBNP-guided therapy or
standard symptom-guided therapy.[65] Patients age 60–74 years were further compared with those age 75 years or
older. All patients had to have at least New York Heart Association (NYHA) functional class II symptoms, history of HF
hospitalization within the past year, and a minimum NT-proBNP level ( 400 pg/mL for patients age 60–74 years; 800
pg/mL for patients age 75 years or older). Goals of therapy were to reduce symptoms to NYHA functional class II or
less or symptoms and NT-proBNP levels to less than two times the normal value. Medical therapy recommendations
were provided based on current guidelines but were ultimately at the discretion of the individual physician. Ultimately,
no difference in the primary outcome of survival-free hospitalization of any cause between groups was seen. Qualityof-life metrics improved in both groups to a similar degree. However, there was a significant association between age
and clinical outcomes, demonstrating that patients younger than 75 years conferred benefit with NT-proBNP-guided
therapy as opposed to older patients.
The BATTLESCARRED (NT-proBNP-Assisted Treatment To Lessen Serial Cardiac Readmissions and Death) trial
compared three treatment strategies: (1) usual care, (2) intensive, standardized, clinically guided care, and (3) NTproBNP-guided care.[66] Patients enrolled had symptomatic congestive HF with a recent hospital admission, and an
NT-proBNP level of >400 pg/mL. Medical therapy in the clinically guided care and NT-proBNP groups was adjusted
based on an HF score with a preset algorithm. Therapy in the NT-proBNP group was also targeted to reduce levels of
NT-proBNP to less than 1300 pg/mL. The primary outcome was all-cause mortality and the composite of death plus
hospitalization for HF. A total of 364 patients were randomized. Overall, mortality at 1 year was significantly improved
in both the NT-proBNP and clinically guided care groups compared with the group receiving usual care. Three-year
mortality was improved with NT-proBNP compared with both clinically guided and usual care but only for patients age
75 years or younger. For the primary endpoints of death and hospitalization for HF, a similar pattern was observed,
except that the benefit at 1 and 3 years was only seen in the younger group of patients.
The addition of NT-proBNP levels to guide medical therapy of patients with HF may be beneficial in certain
populations. This strategy appears to be most useful in younger patients (<75 years). The reasons for this are not
entirely clear but may reflect a greater prevalence of comorbidities, including renal insufficiency, among older patients.
In addition, older patients may be less likely to reach target dosages of certain medications (e.g., ACE inhibitors, blockers) and have more HF with preserved systolic function, for which the importance of these medication classes
and target dosages are less clear. In both the TIME-CHF and BATTLESCARRED trial, NT-proBNP levels fell to a
similar degree between hormone-guided and control groups. In many cases, medical therapy was adjusted even in the
absence of worsening symptoms. This suggests that there may be opportunities to further optimize the management of
HF with or without NT-proBNP guidance.[67] While the BNP or NT-proBNP level itself may be of value in guiding initial
therapy, some authors have suggested that the manner in which these levels are reduced may be even more
important.[67] ACCF/AHA guidelines state that the value of serial measurements of BNP to guide therapy is not well
established (class IIb, level C).[1] HFSA guidelines state that it is not possible to recommend the use of natriuretic
peptides to guide therapy for HF in either the inpatient or outpatient setting until further data become available.[5]
Maintenance Therapies
While the medical management of AHFS largely focuses on symptomatic and hemodynamic improvement, none of the
medications used in this setting have shown an improvement in long-term outcomes. Consequently, clinical practice
guidelines have recently addressed the importance of initiating and optimizing evidence-based oral medications for
long-term use (e.g., ACE inhibitors, angiotensin-receptor blockers [ARBs], -blockers, aldosterone antagonists) at
some point during the patient's hospital stay.[1,5,6] This is a particularly salient point, given that patients are often
discharged on the same pre-admission medications. Aside from diuretic dosage adjustments, initiation of new or
escalation of evidence-based therapies (e.g., ACE inhibitors, -blockers) occurs in less than 10% of patients.[4]
HFSA guidelines recommend that at least near-optimal pharmacologic therapy (e.g., ACE inhibitor and -blocker for
patients with reduced LVEF) is achieved for all HF patients before hospital discharge. Specifically, HFSA recommends
initiating -blocker therapy at a low dose before discharge in stable patients (after optimization of volume status and
successful discontinuation of i.v. diuretics and vasoactive agents; strength of evidence = B). Upward adjustment of
dosages should be gradual (typically every two weeks). For patients who have been receiving long-term maintenance
therapy with a -blocker, HFSA recommends continuation in most patients experiencing a symptomatic exacerbation of
HF (strength of evidence = C) unless there is evidence of cardiogenic shock, refractory volume overload, or
symptomatic bradycardia.[5] Even in this setting, it may be appropriate in some situations to temporarily lower the blocker dosage by half. Beta-blocker therapy should not be abruptly discontinued unless the situation is life threatening
(strength of evidence = C).[5]
ACCF/AHA guidelines provide similar recommendations, stating that oral therapies known to improve outcomes (ACE
inhibitors, ARBs, -blockers) should be initiated in stable patients before hospital discharge (class I, level B). Particular
caution is warranted before starting a -blocker in patients who required an inotrope during their hospital stay. For
patients who have been receiving maintenance oral therapies known to improve outcomes, it is recommended that
these be continued in most patients in the absence of hemodynamic instability or contraindications (class I, level C).[1]
The ESC guidelines are consistent with other guidelines in that ACE inhibitors or ARBs should be initiated before
hospital discharge and continued as maintenance therapy, even for an admission for worsening HF (class I, level A).[6]
After the patient has been stabilized on an ACE inhibitor or ARB, a -blocker should be initiated before hospital
discharge. ESC suggests that the -blocker should generally not be stopped in patients with AHFS, but the dosage
may need to be reduced temporarily or omitted in unstable patients with low output or in cases of severe HF and
inadequate response to initial therapy (class IIa, level B). Although the use of -blockers in patients with AHFS has
historically been controversial, several recent trials and registry data have shown improved outcomes with both
predischarge initiation and continuation of therapy during hospitalization.[68–71]
Finally, only the ESC guidelines address digoxin as a consideration for AHFS as a means of producing a small
increase in CO, reducing filling pressure, and slowing ventricular rate in rapid atrial fibrillation (class IIb, level C).[6]
Despite a lack of data on the role of digoxin in AHFS, some authors have advocated for its reevaluation in this setting
on the basis of favorable hemodynamic, neurohormonal, and symptomatic benefits.[52]
Investigational Therapies
Several therapies with novel mechanisms of action are under investigation for the management of AHFS.[8,9,72] Table 4
provides an overview of select agents that have been studied the most extensively in clinical trials. A host of
vasodilator classes are under development, including adenosine antagonists (rolofylline), atrial natriuretic peptides
(ularitide), peptide hormones (relaxin), and direct renin inhibitors (aliskiren). Rolofylline is an adenosine A1-receptor
antagonist that has been evaluated in the Study of the Selective A1 Adenosine Receptor Antagonist KW-3902 for
Patients Hospitalized With Acute HF and Volume Overload to Assess Treatment Effect on Congestion and Renal
Function (PROTECT-2).[73] This trial showed no benefit of rolofylline over placebo among 2033 patients with AHFS and
impaired renal function in terms of the primary endpoint (treatment success, patient unchanged, or treatment failure).
Higher rates of neurologic events were also seen with rolofylline, including seizures and strokes. Other adenosine
antagonists remain under investigation; paradoxically, adenosine agonists are concurrently in development. In addition
to the investigational agents addressed, the direct renin inhibitor aliskiren is under study for the management of AHFS.
Table 4. Overview of Select Investigational Therapies for Acute Heart Failure Syndromesa
Agent
Classification
Mechanism of Action
Levosimendan
Calcium
sensitizer
Stabilizes calcium–troponin C
Increased contractility and vasodilation;
complex, opens smooth muscle similar effect on mortality vs. dobutamine;
potassium ion channels
approved in Europe
Adenosine
Inhibits adenosine A1-receptor
Rolofylline
Comments
Increased diuresis and natriuresis; no
change or increased GFR; no improvement
antagonist
in afferent arterioles of kidneys
in symptoms or clinical outcome vs.
placebo
Ularitide
ANP
Binds to ANP receptors in
kidneys
Increased diuresis and natriuresis; similar
activity to nesiritide
Relaxin
Peptide
hormone
Releases nitric oxide, inhibits
endothelin and angiotensin II
Decreased cardiac filling pressure and
increased cardiac output
aAdapted
from references 8, 9, and 72. GFR = glomerular filtration rate, ANP = atrial natriuretic
peptide.
Inotropic therapies continue to be explored, including calcium sensitizers (levosimendan), cardiac myosin activators,
metabolic modulators, and Na/K-ATPase inhibitors (istaroxime). Levosimendan has been the most extensively studied
inotropic agent thus far. However, primary results from the Survival of Patients With Acute Heart Failure in Need of
Intravenous Inotropic Support (SURVIVE) trial showed no difference in mortality at 180 days between levosimendan
and dobutamine among 1327 patients.[74] Adverse effects were also more common with levosimendan, including
hypotension, tachyarrhythmias, hypokalemia, and headache.
Conclusion
Drug therapy of AHFS may include diuretics, vasodilators, morphine, ACE inhibitors, digoxin, inotropes, and
vasopressin antagonists. Clinical practice guidelines for patients with AHFS provide a useful mechanism to incorporate
available evidence and standards of practice into patient care.
Appendix—Comparison of Guidelines for Management of Acute Heart Failure Syndromes
[1,5,6]
American College of Cardiology Foundation/American Heart Association,[1,a]
Diuretics
z
z
z
Start i.v. loop diuretics in the emergency department or clinic setting for significant fluid overload (class I, level
B).
The initial i.v. dose should equal or exceed the long-term oral daily dose. Adjust dose according to symptom
relief and to reduce extracellular fluid volume excess (class I, level C).
When diuresis is inadequate to relieve congestion, the regimen should be intensified by using higher doses of
loop diuretic, adding a second diuretic (e.g., metolazone, spironolactone, chlorothiazide), or using a continuous
infusion of loop diuretic (class I, level C).
Vasodilators
z
I.V. nitroglycerin, sodium nitroprusside, or nesiritide added to diuretics or in patients not responding to diuretics
alone for evidence of severely symptomatic fluid overload in the absence of systemic hypotension (class IIa,
level C).
Inotropes
z
z
I.V. inotropic or vasopressor drugs should be administered for clinical evidence of hypotension with
hypoperfusion and obvious evidence of elevated cardiac filling pressure (class I, level C).
Dopamine, dobutamine, or milrinone might be reasonable for patients with severe systolic dysfunction, low
z
blood pressure (BP), and evidence of low cardiac output, with or without pulmonary congestion (class IIa, level
C).
Use of i.v. inotropes in normotensive patients without evidence of decreased organ perfusion is not
recommended (class III, level B).
Heart Failure Society of America,[5,b]
Diuretics
z
z
z
z
Loop diuretic (usually given i.v.) for evidence of fluid overload is recommended (strength of evidence = B).
Use of diuretic doses needed to achieve optimal volume status with relief of signs and symptoms of pulmonary
congestion without causing a rapid reduction in intravascular volume or serum electrolytes (strength of evidence
= C).
Patients with moderate-to-severe renal dysfunction and evidence of fluid retention should continue to be treated
with diuretics. In the presence of severe fluid overload, renal dysfunction may improve with diuresis (strength of
evidence = C).
When congestion fails to improve with diuretics, the following pharmacologic options should be considered:
increasing doses of loop diuretic, continuous infusion of loop diuretic, and the addition of a second type of
diuretic (e.g., metolazone, spironolactone, chlorothiazide) (strength of evidence = C).
Vasodilators
z
z
z
z
I.V. nitroglycerin, sodium nitroprusside, or nesiritide added to diuretics for rapid improvement of congestive
symptoms in the absence of symptomatic hypotension may be considered. Frequent BP monitoring is
recommended (strength of evidence = B).
Reintroduction of i.v. vasodilators in increasing doses may be considered once symptomatic hypotension is
resolved (strength of evidence = C).
I.V. nitroglycerin or sodium nitroprusside and diuretics for rapid symptom relief in patients with acute pulmonary
edema or severe hypertension are recommended (strength of evidence = C).
Sodium nitroprusside, nitroglycerin, or nesiritide in patients with persistent severe heart failure (HF) despite
aggressive treatment with diuretics and standard oral therapies may be considered (sodium nitroprusside:
strength of evidence = B; nitroglycerin and nesiritide: strength of evidence = C).
Inotropes
z
z
z
z
z
z
Milrinone or dobutamine to relieve symptoms and improve end-organ function in advanced HF, particularly with
marginal systolic BP (<90 mm Hg), symptomatic hypotension despite adequate filling pressure, or lack of
response or intolerance to i.v. vasodilators may be considered (strength of evidence = C).
Milrinone or dobutamine with evidence of fluid overload if poor response to i.v. diuretics or
diminished/worsening renal function may be considered (strength of evidence = C).
Vasodilators should be considered over inotropes for adjunctive therapy (strength of evidence = C).
Inotropes are not recommended unless left heart filling pressure is known to be elevated or cardiac index is
severely impaired based on direct measurement or clear clinical signs (strength of evidence = C).
Continuous or frequent BP and cardiac rhythm monitoring with i.v. inotropes is recommended (strength of
evidence = C).
Discontinuation or dose reduction of i.v. inotropes should be considered if symptomatic hypotension or
worsening tachyarrhythmias develop (strength of evidence = C).
European Society of Cardiology,[6,c]
Diuretics
z
I.V. loop diuretic in the presence of symptoms secondary to congestion and volume overload (class I, level B).
Vasodilators
z
I.V. nitrates and sodium nitroprusside in patients with systolic BP of >110 mm Hg (or with caution in patients
with systolic BP of 90–110 mm Hg) (class I, level B).
Inotropes
z
z
z
Inotropes should only be administered in patients with low systolic BP or cardiac index in the presence of signs
of hypoperfusion or congestion (class IIa, level B).
Dobutamine or dopamine (class IIa, level B).
Milrinone (class IIb, level C).
a
Classes of recommendations: I = treatment should be administered, IIa = reasonable to administer treatment
although additional studies with focused objectives needed, IIb = treatment may be considered although additional
studies with broad objectives needed, III = treatment should not be administered since it is not helpful and may be
harmful. Levels of evidence: A = multiple (3–5) population strata evaluated and general consistency of direction and
magnitude of effect, B = limited (2–3) population risk strata evaluated, C = very limited (1–2) population risk strata
evaluated.
b Levels of evidence: A = randomized, controlled, clinical trials, B = cohort and case–control studies, C = expert
opinion. Strength of recommendations: "is recommended" = part of routine care, "should be considered" = majority of
patients should receive the intervention, "may be considered" = individualization of therapy is indicated, "is not
recommended" = therapeutic intervention should not be used.
c Classes of recommendations: I = evidence and/or general agreement that a given treatment is effective, IIa = weight
of evidence/opinion in favor of efficacy, IIb = efficacy is less well established by evidence/opinion, III = evidence or
general agreement that the treatment is not effective and in some cases may be harmful. Levels of evidence: A = data
derived from multiple randomized clinical trials or meta-analyses, B = data derived from a single randomized trial or
large nonrandomized studies, C = consensus of opinion of the experts and/or small studies, retrospective studies, and
registries.
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2009; 54:1343–82.
2. Curtis LH, Greiner MA, Hammill BG, et al. Early and long-term outcomes of heart failure in elderly persons,
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Dr. Murali is a consultant for and serves on the speakers' bureau of Otsuka Pharmaceutical Co., which manufactures Samsca (tolvaptan).
The other authors have declared no potential conflicts of interest.
American Journal of Health-System Pharmacy. 2011;68(1):21-35. © 2011 American Society of Health-System Pharmacists, Inc.
All rights reserved. Posted with permission.