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DECEMBER 2004
A Special Report from the
ADHERE Investigator Meeting
July 15-17, 2004,
New Orleans, Louisiana
Faculty
J. Thomas Heywood, MD
Professor of Medicine
Director, Cardiomyopathy Program
Loma Linda University Medical
Center
Loma Linda, California
This monograph is designed to be a
summary of information. Although it
is detailed, it is not an exhaustive
clinical review. McMahon Publishing
Group, Scios Inc., and the authors
neither affirm nor deny the accuracy
of the information contained
herein. No liability will be assumed
for the use of this educational
review, and the absence of typographical
errors is not guaranteed.
Readers are strongly urged to
consult any relevant primary literature.
Copyright © 2004, McMahon
Publishing Group, 545 West 45th
Street, New York, NY 10036. Printed
in the USA. All rights reserved,
including the right of reproduction,
in whole or in part, in any form.
ADHERE ® :
Improving the Medical
Management and Quality of Care
Of Heart Failure Patients
Introduction
Heart failure (HF) is often treated with
less urgency than other cardiovascular
syndromes, including acute myocardial
infarction (MI), even among patients
admitted to the emergency department
(ED). The reasons for this treatment gap
remain poorly understood. However,
known impediments to optimal patient
care include an inconsistent definition of
HF, a lack of protocols or order sets to
address acute decompensated heart failure
(ADHF), a poor understanding of HF
management guidelines, less stringent
care for patients who are less symptomatic,
failure to identify patients at high
risk of death, and poor communication
among caregivers. If ADHF were
approached with the same urgency and
attention as MI, patient and hospital outcomes
could be improved.
This Special Report describes new
approaches to the management of ADHF,
the use of various pharmacologic agents,
and the role of ADHERE (the Acute
Decompensated Heart Failure National
Registry) in collecting patient data
and national trends in HF management
and outcomes.
The ADHERE Registry
The ADHERE Registry contains information
on more than 140,000 hospital admissions
at over 280 participating hospitals
between October 2001 and July 2004.
Because of the high rates of morbidity,
mortality, and management cost associated
with HF, an analysis of practice patterns
and clinical outcomes in a large population
of hospitalized HF patients can identify
opportunities for improvement in care and
for closing gaps in treatment.
There are approximately 1 million hospitalizations
for HF each year in the United
States. Although hospitalizations for other
heart diseases are on the decline, the
number of HF hospitalizations is increasing.
1 Of patients who are hospitalized for
HF, almost half will be readmitted at least
once within 6 months after their index hospitalization.
2 More than half of readmissions
for HF are associated with a lack of
patient compliance with medical and
dietary prescriptions, inadequate followup,
inadequate patient education, or
failed social support. 3,4 Thus, most HF
readmissions are preventable.
Even with the advent of angiotensinconverting
enzyme (ACE) inhibitors,

2
Table 1. Demographics, Clinical Characteristics,
And Outcomes of the ADHERE Population
Enrolled Discharges*
October 2001–January 2004 (n=105,388)
Age, y (mean) 75.0
Gender
Female
Male
Race/ethnicity
Caucasian
African-American
Hispanic
Medical history
Coronary artery disease
Hypertension
Myocardial infarction
Diabetes mellitus
Chronic renal insufficiency
Chronic dialysis
Ventricular tachycardia
Atrial fibrillation
Clinical outcomes
In-hospital mortality
Hospital LOS, d
(median)
ICU LOS, d (median)
52
48
72
20
3
57
72
31
44
30
5
9
31
β-blockers, aldosterone antagonists, and other effective
treatments, approximately 12% of patients who are hospitalized
for ADHF die within 30 days after admission. One
third die within 1 year of their index hospitalization. 5
These morbidity and mortality rates are unacceptably
high, given the availability of evidence-based treatments
for HF.
The direct and indirect costs of treating patients with HF
exceed $28 billion annually, 1 and the greatest proportion
of these costs are accounted for by in-hospital management.
Almost 80% of patients with HF who arrive at the ED
are eventually admitted to the hospital, so ED care plays a
critical role in patient outcomes.
The ADHERE data show that patient demographics for
those who are hospitalized with HF differ from those of HF
patients selected to participate in clinical trials (Table 1). 6
For example, many clinical trials exclude patients with HF
who have renal insufficiency or a left ventricular ejection
fraction (LVEF) of greater than 40%, yet at least 50% of
patients in the ADHERE Registry have an LVEF of more
than 40%. Patients with preserved systolic function may be
just as ill as patients with systolic dysfunction and may be
harder to treat.
The registry also collects data on HF management
that are useful in developing optimized care plans. For
example, most patients with HF do not receive a
diuretic for almost 8 hours after they are admitted and
do not receive a vasoactive drug for almost 24 hours
after admission. Further, although ACE inhibitors and
β-blockers are effective in patients with HF regardless of
4.0
4.3
2.5
*Values are percentage of patients unless otherwise noted.
d, days; ICU, intensive care unit; LOS, length of stay; y, years
Data from the ADHERE Registry, January 2004. 6
the etiology or the stage of the disease, only about 50%
of eligible ADHF patients receive ACE inhibitors or
β-blockers as chronic oral therapy, and a very small percentage
receive aldosterone antagonists (Figure 1).
These multicenter data highlight the need to provide
caregivers with standard protocols for ADHF treatment
so that optimal care can be applied widely and consistently
in this large population.
Among ADHERE Registry patients, approximately 88%
received I.V. diuretics after hospital admission. 6 Although
diuretics are standard therapy for ADHF, they have not
been evaluated in large, randomized trials and are not
without risks. Numerous studies have shown that diuretics
reduce intravascular volume and glomerular filtration
rate (GFR) and further activate the neurohormonal system—which,
ideally, should be inhibited to attenuate HF. 7,8
In a substudy of the SOLVD (Studies of Left Ventricular
Dysfunction) trial, patients treated long-term with oral
diuretics had increased all-cause mortality, cardiovascular
death, and sudden cardiac death. 9 In addition, 10% of
ADHERE patients continue to receive inotropes, 6
although their use is associated with an increased risk of
arrhythmias and other adverse events. 10
The Joint Commission on Accreditation of Healthcare
Organizations (JCAHO) specified 4 quality-of-care indicators
that are not optimally met among ADHERE patients:
instruction on diet, weight, and medication management
at discharge (HF-1); assessment or scheduling of assessment
of left ventricular systolic function (HF-2); ACE
inhibitor use at discharge in patients considered candidates
for this therapy (HF-3); and counseling on smoking
cessation in current smokers (HF-4) (Table 2). In a study
by Krumholz et al, 14% of patients eligible for ACE
inhibitors were not prescribed these agents, and in a subgroup
of patients who did receive ACE inhibitors, 14% did
not receive the target dose. 11 Collectively, these and other
data suggest that proven therapies continue to be underused
and that there are clear areas for improving the
quality of care for HF patients. 12
Clinical care and treatment rates in the ADHERE
Registry vary significantly, but optimal care is an achievable
goal.
Factors Associated With Mortality
And Resource Use in the ADHERE
Registry Database
The overall mortality in the ADHERE Registry is 4.0%
(calculated on the basis of 105,388 admissions). 6 However,
subgroup analyses have demonstrated large differences
among groups. Anemia (hemoglobin level
1.5 mg/dL) are associated with
increased mortality (Table 3, page 4), and patients with
anemia, renal insufficiency, and diabetes mellitus use
more hospital resources.
There is an overlap among risk factors: patients with
anemia tend to have both higher blood urea nitrogen
(BUN) and higher SCr levels. Similarly, diabetic patients

100
90
80
80.8
Patients Treated, %
70
60
50
40
30
50.8
57.4
41
20
10
0
12.8
ACE Inhibitor ARB β-Blocker Digoxin Diuretic
Outpatient HF Medication
Figure 1. Use of oral therapies at admission among patients with ADHF who have a documented LVEF of
43 mg/dL
• systolic blood pressure 2.75 mg/dL
Patients without these 3 risk factors have an average inhospital
mortality risk of only 2%, but patients with all 3 risk
factors have an in-hospital mortality risk of 22%. 13 Patients
with 1 or 2 risk factors have an intermediate in-hospital
Table 2. Quality of Care in the ADHERE Population: Conformity to JCAHO Heart Failure
Performance Indicators*
Performance Indicator
All Patients
(n=105,381)
Patients at
Academic
Hospitals
(n=34,346)
Patients at
Nonacademic
Hospitals
(n=71,035)
P Value**
HF-1, patient instruction on diet, weight, and medication
management at discharge
HF-2, assessment or scheduling of assessment of left
ventricular systolic function
HF-3, ACE inhibitor use at discharge in patients
considered candidates for this therapy on the basis of
accepted clinical criteria
32.3 21.9 37.8

Table 3. Effects of Comorbidities on Outcomes in ADHERE Patients
Outcome Anemia
Renal Insufficiency Diabetes
Yes No Yes No Yes No
No. of patients 20,151 24,693 13,366 33,125 20,444 26,155
Hospital LOS, d 6.3* 5.6 6.6* 5.6 6.2* 5.7
Mortality, % 4.8* 3.3 5.7* 3.5 4.1 4.1
d, days; LOS, length of stay
*P

healthcare costs. Many of these kits contain a treatment
algorithm, an ED-specific order set, admission and discharge
order sets, and discharge counseling material.
The Cardinal Atlas database and the ADHERE Registry
have provided data for developing guidelines as well as
algorithms based on real-world patient data and
evidence-based data on HF medical management. For
example, there are no specific HF guidelines for the timing
of treatment. However, the ADHERE data, in combination
with what is known about other acute situations,
such as sepsis and septic shock, are guiding the development
of algorithms for the aggressive management of
ADHF. 18,19 In addition, because renal insufficiency is a
major predictor of poor outcomes and is associated with
high costs, guidelines for some programs include specifications
for triaging patients with specific renal markers
and for using nesiritide with a lower dose of a diuretic.
Early Diagnosis and Management
Of HF in the ED
Most HF patients who are admitted to the hospital first
receive care in the ED. Subsequent patient management
has a substantial impact on outcomes and cost. For
example, a transfer to the intensive care unit (ICU) is more
expensive than a transfer to a telemetry unit, a regular
floor, or an observation unit (OU).
Expenses accrue with HF misdiagnosis in primary care
and ED settings. For example, if a patient is misdiagnosed
as having chronic obstructive pulmonary disease and is
treated with albuterol, hours to days of appropriate treatment
will be lost and hospital LOS increased. Delaying the
initiation of combination therapies while observing the
results of diuretic treatment alone can hinder appropriate
care and increase hospital LOS.
A BNP assay is currently used by about 50% of the
hospitals in the United States. BNP levels are closely
associated with New York Heart Association functional
class, so they provide prognostic value as well as diagnostic
accuracy. BNP levels are highly specific and sensitive
for distinguishing patients with HF from those with
other conditions when the chief complaint is dyspnea. 20
The negative predictive value of this test is 91% to 98%,
but the positive predictive value is 85% to 92%, depending
on the BNP level. 20
A number of factors, including old age, higher body
mass index, and history of hormone replacement therapy,
can obscure BNP levels. Cirrhosis elevates BNP levels
3 times beyond baseline, dialysis increases BNP
levels 25 times above baseline, and an MI or renal failure
increases BNP levels as well. A high BNP level
(≥500 pg/mL) indicates that HF is very likely, and a low
BNP level (

Diuretic,
vasodilator
Cardiac Index
2.2
L/min/m
2
Subset I
(normal)
Warm & Dry
Subset III
(hypoperfusion)
Subset II
(pulmonary
congestion)
Warm & Wet
Subset IV
(hypoperfusion &
pulmonary congestion)
Inotrope,
diuretic,
vasodilator
67%
Warm & Wet
28%
Cold & Wet
Cold & Dry
Cold & Wet
5%
Cold & Dry
Inotrope
18 mm Hg
Pulmonary Capillary Wedge Pressure
Figure 2. Hemodynamic subsets among patients presenting with ADHF.
ADHF, acute decompensated heart failure
Adapted with permission from Fonarow. 40
Pharmacoeconomic Evaluation of Nesiritide
Evaluations of costs associated with particular medication
regimens can help refine protocols and treatment
strategies, especially if a comprehensive evaluation
includes key outcomes. Nesiritide provides a benefit to
HF patients through a combination of hemodynamic,
neurohormonal, and renal effects. 26 Nesiritide improves
cardiac index through balanced vasodilation, producing
dose-dependent reductions in mean arterial pressure,
right arterial pressure, systolic blood pressure, pulmonary
capillary wedge pressure, and systemic vascular
resistance. 26-31 It also favorably affects the autonomic dysfunction
that occurs in HF, as seen in the improvements
that occur in moderately and severely depressed heart
rate variability with treatment, 32 and decreases concentrations
of deleterious neurohormones, including aldosterone,
norepinephrine, and endothelin-1. 26,27,31,33,34
Nesiritide exerts activity at the proximal and distal segments
of the renal tubule, causing dose-dependent
increases in natriuresis and diuresis. 27,29,33,35 It is considered
a safe and effective treatment for ADHF. 36
A recent study evaluated the cost and outcomes of
nesiritide use. In this retrospective case–control study,
patients admitted to the hospital for HF (DRG 127 or 428)
were assigned to receive nesiritide within the first 48
hours after hospitalization, infused for 12 hours or more,
or not to receive this treatment. 37 The nesiritide-treated
patients (n=108) spent less time in the coronary care unit
(CCU) (105.3 vs 82.6 hours; P=0.03), demonstrated a
trend toward lower in-hospital and 90-day mortality, and
demonstrated a trend toward lower overall rehospitalization
rates than case-matched controls not treated with
nesiritide. In addition, there was a significant difference in
cost (P=0.027), amounting to a savings of $1,446 for the
nesiritide-treated group. The nesiritide-treated patients
also experienced significantly less renal failure and atrial
fibrillation. 37 These analyses suggest that nesiritide use in
patients with ADHF is cost-effective, since it reduces
readmissions and hours spent in the CCU, promotes
hemodynamic improvement and diuresis, and decreases
the need for prolonged hospitalization due to electrolyte
imbalances or renal dysfunction. In another study, Chang
et al found that the addition of nesiritide to standard therapy
reduced hospital LOS by 1 day. 38
The Merits and Challenges
Of Disease Management
Hemodynamic profiles of HF patients can help guide
appropriate treatment. Overall, 49% to 67% of patients
have normal perfusion with pulmonary congestion and,
thus, are considered “warm and wet”; 20% to 28% of
patients have hypoperfusion and pulmonary congestion
and are considered “cold and wet”; and only 4% to 5% of
patients typically have hypoperfusion without pulmonary
congestion and are considered “cold and dry” (Figure
2). 39-41 Therefore, the majority of patients are expected to
respond to diuretics and vasodilators. Consistent order
sets and protocols can help ensure appropriate treatment,
including the use of ACE inhibitors and β-blockers
for eligible patients.
A hospital-based disease management program not
only ensures appropriate order sets and medication use
but also can directly affect outcomes. Several studies have
shown a direct association between inpatient care and outcomes
such as mortality and readmission rates. 42,43 Additional
studies indicate that other aspects of disease
management such as discharge planning and patient education
can also decrease readmissions and poor
6

outcomes. 4,44 Hospitals participating in the ADHERE Registry
receive regular performance comparisons with
regional hospitals and participating ADHERE hospitals
across the nation. These reports allow assessment of outcomes
such as in-hospital mortality and average hospital
LOS; the percentage of patients who are admitted through
the ED; JCAHO performance indicators including the percentage
of patients who receive ACE inhibitors; and use of
the ICU and number of invasive procedures.
Many hospitals are initiating performance improvement
or disease management programs to improve outcomes
and decrease costs. Common goals include
decreasing hospital LOS, cost, and readmission rates;
improving performance on JCAHO indicators; and optimizing
the use of HF medications. Achievement of these
goals involves developing admission and discharge
order sets, diuresis and vasodilator protocols, dosing
guidelines, ED components, outpatient components, and
a mechanism to measure performance improvement.
The steps for creating a performance improvement plan
include developing tools, providing physician education,
conducting pilot trials, evaluating and revising existing
protocols, and, eventually, implementing these steps on a
hospital-wide basis.
There are numerous barriers to implementing a hospital-based
disease management program. Moreover, a
multidisciplinary hospital-based program may take a significant
amount of time to implement. One option is to
work with a less diverse but targeted staff to implement a
pilot program. The targeted staff should include ED personnel,
cardiology staff, and staff members who admit a
large number of patients, such as internal medicine and
family practice physicians. Their initial meeting should
include discussion of the clinical and economic rationales
for developing guidelines, the development of early
aggressive intervention protocols and order sets, an
implementation plan for incorporating the guidelines, and
the development of hospital self-assessment forms to
measure process improvement.
Medication Use Evaluation
Medication use evaluation (MUE) can assess and
improve medication use with the goal of optimizing
patient outcomes. 45 It is a process that sets standards for
best practices and promotes cost-effective therapy. MUE
may be applied to a particular medication or an entire
therapeutic class, a disease state or condition, a system
of medication use (eg, prescribing, preparing and dispensing,
administering, monitoring), or a specific outcome
such as mortality reduction.
Although historically MUEs have been performed in
hospitals, they can easily be performed in other practice
settings, such as outpatient clinics that manage HF. Ideally,
an MUE is conducted as a proactive, criteria-based
process. It should be institutionally authorized, and
designed and managed by an interdisciplinary team. 45
However, retrospective MUEs can also be used to identify
areas where further education or training is necessary.
The MUE process should be systematic. For example, an
MUE is most effective if guidelines and treatment protocols
are developed and implemented at the same time
that medications are available.
The main goals of the MUE are to promote optimal
medication therapy, prevent medication-related problems,
evaluate the effectiveness of therapy, and improve
patient safety. 45 Minimizing procedural variations in
treatment by standardizing the use of particular medications
is one example. This action effectively decreases
the chance of error and could reduce indirect costs
associated with therapy, such as the management of
side effects and drug–drug interactions. The MUE
should have a mechanism for data collection and
screening, priorities for review and analysis, and a procedure
for communicating program objectives and expected
benefits. 45
Typically, an MUE is conducted on medications that are
expensive, are suspected of causing adverse reactions, or
are used by patients at high risk for developing adverse
reactions. Medication use processes may also be evaluated
if the agent is prescribed to many patients or if the
process of use itself (eg, timing of administration) is an
important component of care for a condition. 45 The introduction
of a new medication provides an opportunity to
review an overall treatment strategy and may uncover problems
in other areas of medical management, including
safety, cost, administration, and monitoring.
The MUE should be reviewed regularly and should be
designed so that the evaluation methodology does not
impede care. 45 The MUE is a useful tool for evaluating the
process and the appropriateness of therapy and for controlling
cost. It can provide data to support the use of
higher-cost therapies in exchange for other patient or
institutional benefits. In most institutions, pharmacy
administrators are the driving force behind the MUE; they
plan, collect and interpret data, report findings, and provide
MUE recommendations.
Conclusion
Data gleaned from the ADHERE Registry and other
sources underscore the need for the use of algorithms
and systems for managing ADHF and for recognizing
comorbid conditions in patients with HF. Worsening renal
function portends an ominous prognosis in HF, and a systematic
approach to the patient with concomitant HF and
renal insufficiency may result in improved outcomes.
Nesiritide, adenosine receptor antagonists, and vasopressin
antagonists may provide nondiuretic means for
fluid removal in fluid-overloaded patients. Evidencebased
research recommends against continued use of
inotropic agents, less than optimal ACE inhibitor use or
dosing, and use of diuretic monotherapy in the treatment
of HF patients with and without comorbid conditions, but
use of these therapies continues. New approaches to
ADHF are needed to reduce treatment delays, improve
clinical outcomes, and mitigate the economic burden of
this disease.
7

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