US Pharm. 2013;38(2):HS2-HS8.
ABSTRACT: Acute decompensated heart failure
(ADHF), an exacerbation of chronic cardiac, pulmonary, and/or renal
dysfunction, accounts for most of the $39 billion spent on chronic heart
failure. The pharmacotherapy of ADHF has not changed recently, but
studies have indicated that most therapy is efficaciously, though not
economically, equivalent. Evidence-based, inpatient pharmacotherapy is
guided by understanding of the Forrester Hemodynamic subsets and their
pathophysiology. Clinical success is dependent not only upon proper
inpatient treatment, but also upon the utilization of a discharge team.
Pharmacists can bridge the gap between hospital visits and outpatient
care by recommending and providing continuity of care.
In 2010, the cost of treating heart failure (HF) in the United States was estimated at $39.2 billion.1,2
Nearly 1 million patients are hospitalized each year for exacerbations,
and HF currently ranks as the most common reason for hospital admission
in adults over 65 years of age.2 Acute decompensated heart
failure (ADHF) can result from poorly controlled, chronic HF and/or
cardiac, pulmonary, or renal dysfunction. The inpatient cost of care for
these patients is extremely high, accounting for about 60% of total HF
In addition to the financial impact of HF, longevity and
quality of life are severely impacted in patients with acute
exacerbations. Hospital admission is associated with an increased risk
of mortality in HF patients; mortality occurs in 15.5% of patients, and
one-third of patients are never discharged from the hospital.2 ADHF is a crippling disease burdening not just patients, but also the health care system.
ADHF pharmacotherapy is a battleground for hospitals
seeking to control costs in an era of reduced payments and increased
expenses. In October 2012, the Centers for Medicare and Medicaid (CMS)
began cutting reimbursements to hospitals with high rates of patient
readmissions in three high-cost disease states: myocardial infarction
(MI), pneumonia, and HF. If patients with these conditions are
readmitted within 30 days, CMS will reduce total base reimbursement by
1% annually, until a maximum 3% reduction by 2014.4 Soon,
financial loss will motivate the nearly 2,000 hospitals suffering the
highest penalties to institute new policies and follow-up care for
patients discharged with a diagnosis of HF.
Fortunately, a 2011 analysis by CMS showed that the rate of HF admissions had actually decreased over a 10-year period.1 In 2008, there were 229,000 fewer admissions than expected given observed trends over the past several decades.1,5
Researchers attributed this decline to “reductions in the incidence of
coronary artery disease, improved control of blood pressure, increased
use of evidence-based therapies, and possibly changes in admission
thresholds.” The rate of 1-year all-cause mortality, however, remained
high at approximately 30% for patients hospitalized due to HF.1,5
Black males and certain regions in the country fared worse in rates of
hospitalization; researchers hypothesized that differences in
accessibility or quality of care could contribute to this disparity.1
The best outcomes (reduced costs and readmission rates) are seen with a
multidisciplinary approach that includes physicians, pharmacists,
nurses, nutritionists, and physical therapists.6 This article
is a brief review of ADHF pharmacotherapy with an additional look at
pharmacoeconomic considerations and discharge controversies.
ADHF is defined as a sudden worsening of HF symptoms and
is usually caused by cardiogenic pulmonary edema with rapid fluid
accumulation in the lungs, although it can occur without pulmonary
edema.7 Hypertension, ischemia, and/or ventricular
dysfunction causes a decrease in cardiac output, which leads to an
activation of the neurohormonal pathway. The sympathetic system
increases norepinephrine to improve peripheral perfusion via
vasoconstriction and activates the renin-angiotensin-aldosterone system
to increase renal perfusion through water retention.8 An
acute increase in left ventricular filling pressure causes protein-poor
fluid to leak into the lung alveoli and interstitium, but no compromise
of pulmonary membrane integrity occurs. Compensatory mechanisms increase
heart rate and systemic vascular resistance in an attempt to improve
cardiac output, and a vicious cycle ensues.7,8
Common causes of ADHF include left ventricular or
diastolic dysfunction with or without coronary artery disease (CAD) or
valvular abnormalities. Although most patients hospitalized with ADHF
have a worsening of preexisting HF, up to 20% of patients have no prior
diagnosis of HF.9
ADHF can also occur in patients without any preexisting
cardiac disease, including conditions such as severe hypertension, fluid
overload, severe renal disease, or renal artery stenosis. Factors
precipitating an event involve a change in the flow of blood through the
heart; ADHF can be induced by hypertensive crisis, MI or ischemia,
atrial obstruction, acute mitral regurgitation, fluid overload, or
nonadherence to HF medications. Certain medications, such as
beta-blockers, nondihydropyridine calcium channel blockers, and
nonsteroidal anti-inflammatory drugs (NSAIDs), can also precipitate
ADHF can be categorized into hemodynamic stages depending
on cardiac index and pulmonary capillary wedge pressure. The stages are
classified as the Forrester Hemodynamic subsets (TABLE 1).11
Cardiac index (CI) indicates the degree of perfusion; patients are
characterized as either “warm” or “cold” depending on the presence of
hypoperfusion. A CI of <2.2 L/min/m2 warrants a
classification of “cold,” indicating hypoperfusion. Signs and symptoms
consistent with hypoperfusion include fatigue, hypotension, cool
extremities, decreased renal function, and altered mental status.
Pulmonary capillary wedge pressure (PCWP) indicates fluid status;
patients are classified as either “dry” or “wet” depending on the
presence of edema, which is defined as a PCWP >18 mmHg. Signs and
symptoms of volume overload include cough, dyspnea, paroxysmal nocturnal
dyspnea, elevated jugular venous pressure, peripheral edema, ascites,
hepatomegaly, and splenomegaly.
The most common presentation, constituting two-thirds of ADHF admissions, is subset II (warm and wet).8 In comparison to subset I (warm and dry), subset IV (cold and wet) increases the rate of death by two and one-half times.12
Three key laboratory parameters indicate an increased risk of inpatient
mortality according to the Acute Decompensated Heart Failure National
Registry (ADHERE) trial: a blood urea nitrogen of ≥43 g/dL, systolic
blood pressure <115 mmHg, and/or serum creatinine >2.75 mg/dL.13
Pharmacologic management of ADHF is guided by the patient’s hemodynamic status, which is evaluated using CI and PCWP values (TABLE 1).11 The goals and medications for treatment of ADHF are summarized in TABLES 2 and 3.8,14-16
While the standard of care has not changed significantly over the past
several years, a new focus on the pharmacoeconomic impact of HF has
shown that not all treatments are equal. Pharmacotherapy should be
chosen based on the diagnosed subset, either treating fluid overload or
hypoperfusion. Patients in subset IV are classified as having both fluid
overload and perfusion dysfunction and, therefore, require therapy for
Subset II or IV—Wet: Intravenous (IV)
loop diuretics are the mainstay of ADHF treatment for patients
presenting with fluid overload (PCWP >18 mmHg), despite conflicting
data regarding mortality and morbidity benefit. A meta-analysis of 14
small trials showed decreased mortality and hospitalizations in
diuretic-treated patients17; however, a recent analysis of
observational data from the ADHERE trial showed that hospitalized
patients treated with IV diuretics had a longer overall length of stay
and a longer ICU length of stay.18 Regardless, the 2009
focused update of the American College of Cardiology/American Heart
Association (ACC/AHA) guidelines for treatment of HF recommends early
administration of IV diuretics.14 Bolus doses of loop
diuretics are preferred. Furosemide is most commonly used; however,
bumetanide and torsemide are equally efficacious. If patients have
inadequate response to the maximum recommended bolus dose of a loop
diuretic, continuous infusion of furosemide may be started at 5 mg/h and
titrated to 20 mg/h as needed.14
The superiority of administering furosemide as continuous
infusion has yet to be established; the Diuretic Optimization Strategies
Evaluation (DOSE) trial, which studied 308 hospitalized patients
randomized to receive either bolus or IV furosemide, did not show a
significant difference between safety and efficacy endpoints, but
smaller studies have indicated a small increase in urinary output with
continuous infusion.19 The unmanaged effects of rapid
diuresis, such as electrolyte imbalances and renal dysfunction, may lead
to prolonged hospitalization beyond the resolution of ADHF symptoms, so
electrolytes and serum creatinine should be monitored frequently.
Another strategy to increase diuresis is to add a second
diuretic with a different mechanism of action such as metolazone or
spironolactone. Metolazone, a thiazide-like diuretic, is utilized most
frequently for acute volume control; however, spironolactone and other
aldosterone antagonists are preferred in chronic HF therapy.20-22
In patients with continued hypertension and/or persistent
symptoms despite aggressive diuresis, a vasodilator may be added to
reduce pulmonary congestion. Sodium nitroprusside, nesiritide, and IV
nitroglycerin are venous vasodilators that quickly relieve congestive
symptoms by reducing PCWP. If a patient presents with low cardiac output
and high systemic vascular resistance, venous vasodilators or inotropes
are recommended, although vasodilators are the preferred therapy. Due
to the risk of cyanide toxicity from prolonged, high-dose infusions of
nitroprusside, the preferred vasodilators are nesiritide and
nitroglycerin. Of the two, nesiritide produced a greater improvement in
global clinical status over nitroglycerin in the Vasodilation in the
Management of Acute Congestive Heart Failure (VMAC) trial despite the
drug’s propensity to cause hypotension.13 Therefore, nesiritide is the preferred agent in a patient with fluid overload and low cardiac output.
The utility of nesiritide has been questioned because of its high acquisition cost.23
Clinical outcomes data are lacking, but one pharmacoeconomic model
shows that the high initial cost of nesiritide is offset by the lower
rate of hospital readmission within 21 days when compared to patients
who received dobutamine.24 Similarly, a retrospective
analysis of ADHERE data showed that patients treated with nitroglycerin
or nesiritide were discharged from the hospital sooner than patients
treated with dobutamine or milrinone and also had a lower mortality
risk.13 Since more critically ill patients were treated with
inotropes, it is difficult to attribute the incidence of increased
mortality to the drug.
Subset III or IV—Cold: Dobutamine and
milrinone are the inotropes of choice to increase perfusion and
preserve end-organ perfusion in patients with decreased cardiac output.
Compelling indications for inotropes include systolic blood pressure
<90 mmHg, symptomatic hypotension despite adequate filling pressures
(PCWP 15-18 mmHg), worsening renal function, or inadequate response to
IV vasodilators. Prudent selection of patients is necessary because data
suggest poor outcomes occur when inotropes are given to patients with
preserved cardiac output. The OPTIME-CHF trial showed a nonsignificant
increase in mortality and arrhythmias when milrinone infusions were
given to patients as a part of standard care.25 Milrinone
should be chosen to treat patients receiving concomitant beta-blockers
since it exerts an effect on cardiac output and systemic vascular
resistance via phosphodiesterase inhibition, whereas dobutamine is a
beta1 agonist. Dobutamine, however, is the best choice for
hypotensive patients, as milrinone can cause significant drops in blood
The final step in the treatment of ADHF is discharge
planning and follow-up. Both the ACC/AHA and the Heart Failure Society
of America (HFSA) guidelines advocate the importance of proper discharge
planning.14,15 Mainstays of evidence-based discharge care
include treating exacerbating factors, such as discontinuing
nondihydropyridine calcium channel blockers or NSAIDs, achieving optimal
volume state, optimizing pharmacologic therapy, and transitioning to
outpatient oral therapy (TABLE 4).15 The ACC/AHA
guidelines recommend giving written instructions or educational material
to patients and/or caregivers at discharge addressing the following:
activity level, diet, discharge medications, follow-up appointment,
weight monitoring, and what to do if symptoms worsen.14
Guidelines also indicate the benefit of initiating mortality-lowering
oral therapy for HF during hospital admission, such as
angiotensin-converting enzyme (ACE) inhibitors and beta-blockers.
Studies show that guideline-based care decreases mortality,26 but fails to show reduction in readmission rates for patients with HF.27,28
Discharge support, or hospital-based case management, is
now being utilized for discharge planning. Discharge support is a
multidisciplinary, team-based approach to care that deals with
medication support, patient education, follow-up planning, and
coordination of information. A meta-analysis of 18 randomized,
controlled trials (RCT) analyzing discharge planning with postdischarge
support involving 3,304 patients found a significant reduction in
all-cause readmissions (relative risk [RR] 0.75, 95% CI 0.68-0.88).29
The external validity of the meta-analysis is difficult to determine
but may offer some cost-effective strategies. One strategy is from an
RCT of 223 HF patients that compared traditional discharge support with
educational materials to a 1-hour, one-on-one teaching session with a
nurse educator prior to discharge.30 The nurse intervention
group had lower risks of rehospitalization or death 180 days after
discharge and was estimated to save $2,823 per patient. Conversely,
large-scale observational studies have found no relationship between
patients receiving educational materials and decreased readmission
rates.26,31 Current ACC/AHA guidelines do not explicitly
state how to discharge patients after ADHF other than by giving
educational materials.14 Guideline recommendations may not provide discharge procedures that help hospitals comply with CMS expectations.
While educational materials at discharge did not show a
mortality benefit, each additional oral agent used for the treatment of
HF, such as a beta-blocker or aldosterone antagonist, can decrease
hospitalizations and/or mortality by 25% to 35%. ACC/AHA guidelines
suggest that many HF patients are discharged before optimal volume
status is achieved or sent home without the benefit of life saving
therapies, which perpetuates the quick readmission of such patients.14
A hospital pharmacist should be an advocate for patients in the
discharge support team by assisting with medication reconciliation,
discontinuing contraindicated medications, and recommending
evidence-based HF pharmacotherapy. Medications should be initiated as
soon as possible, ideally in the hospital setting; the initiation of
these drugs may exacerbate HF symptoms precipitating ADHF, which further
highlights the importance of timely follow-up for this patient
ADHF is a burden to patients, health care providers, and
payers. The pharmacotherapy for ADHF has not changed recently, but the
utilization of discharge support teams and rapid follow-up after
discharge provide opportunities for pharmacist intervention, both in and
out of the hospital. Community pharmacists can play a large role in the
continuity of care, helping transition patients from hospital to
primary care. Pharmacists are poised to offer proper guideline-based
recommendations, assist with medication reconciliation, and provide
discharge education. With the recent changes in CMS reimbursement,
pharmacists need to take a larger role in the treatment of this chronic
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