REVIEW ARTICLE
Cost-effectiveness Analysis in Clinical Practice
The Case of Heart Failure
Michael W. Rich, MD; Robert F. Nease, PhD
H
eart failure is the leading cause of hospitalization in adults older than 65 years, and it is
currently the most costly cardiovascular disorder in the United States, with estimated
annual expenditures in excess of $20 billion. Recent studies have shown that selected
pharmacological agents, behavioral interventions, and surgical therapies are associated
with improved clinical outcomes in patients with heart failure, but the cost implications of these diverse treatment modalities are not widely appreciated. In this review, a brief outline of costeffectiveness analysis is provided, and current data on the cost-effectiveness of specific approaches to
managing heart failure are discussed. Available evidence indicates that angiotensin converting enzyme inhibitors, other vasodilators, digoxin, carvedilol, multidisciplinary heart failure management
teams, and heart transplantation are all cost-effective approaches to treating heart failure; moreover,
some of these interventions may result in net cost savings. Arch Intern Med. 1999;159:1690-1700
Heart failure affects an estimated 4.9 million Americans, and approximately
400 000 new cases are diagnosed each
year.1,2 In 1995, there were 872 000 hospital admissions attributed primarily to
heart failure, and there were an additional 1.8 million admissions with heart
failure as a secondary diagnosis.2,3 Approximately 80% of all heart failure admissions occur in individuals older than
65 years, and one fifth of all admissions
in that age group have a primary or secondary diagnosis of heart failure.2,3 As a
result, heart failure is the leading indication for hospitalization in older adults.1-3
From 1980 through 1993, the number of physician office visits for heart failure increased by 71%, from 1.7 million to
2.9 million annually.2 In addition, more
than 65 000 patients with heart failure receive home health care each year.2 Moreover, in 1995, heart failure was listed as
the primary cause of death in more than
43 000 cases and as a contributory cause
in an additional 220 000 cases,1,2 and more
than 90% of heart failure deaths occurred in patients older than 65 years.4
From the Geriatric Cardiology Program and the Division of General Medical Sciences,
Barnes-Jewish Hospital, Washington University School of Medicine, St Louis, Mo.
Because of its high prevalence and associated high medical resource consumption, heart failure is now the single most
costly cardiovascular illness in the United
States, with total costs for 1998 estimated at $20.2 billion.1 Remarkably, heart
failure hospitalization costs in 1991 exceeded those for all cancers and all myocardial infarctions combined.5 Moreover,
in contrast to recent declines in ageadjusted mortality rates from coronary
heart disease and hypertensive cardiovascular disease,6,7 the incidence and prevalence of heart failure are increasing, largely
owing to the aging of the population.8 As
a result, the costs of caring for patients with
heart failure are expected to escalate well
into the 21st century.
For these reasons, the last 2 decades
have witnessed a remarkable explosion in
heart failure research, and many new therapeutic options are now available. In addition, there has been considerable interest in
defining the costs associated with heart failure management and identifying those interventions that are most efficacious from
both the clinical and cost perspectives. In
this review, a brief discussion of costeffectiveness analysis is provided, followed by a summary of currently available
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data relevant to the costs of treating
patients with heart failure.
COST-EFFECTIVENESS
ANALYSIS
The goal of cost-effectiveness analysis is to estimate the monetary
cost required to achieve a gain in
health benefit. More specifically,
cost-effectiveness analysis estimates the incremental cost
required to improve a selected
clinical outcome by 1 unit (eg, cost
per year of life saved, cost per
stroke prevented).9,10 The goal is
not to define the greatest benefit at
the lowest cost, since in most cases
it will not be possible to achieve
both simultaneously.
Calculating the cost-effectiveness ratio requires estimating
the change in cost associated with a
given intervention (ie, the numerator of the ratio), as well as the
change in health benefit provided
by that intervention (ie, the
denominator of the ratio). The
notion of incremental costs and
incremental benefits is crucial for
cost-effectiveness analysis. Thus,
the question posed is often of the
form: “What is the monetary cost
of moving from intervention X to
intervention Y in relation to the
associated change in health benefit
in moving from X to Y?”
In estimating the cost-effectiveness ratio, cost is typically measured in dollars. Health benefit, however, may be expressed in a variety
of ways. In cost-benefit analysis, both
the costs and benefits are expressed in monetary terms (ie, the
cost outlay is compared with the
monetary value of the benefits obtained).11 Because it is often difficult to place a monetary value on a
clinical benefit (eg, how much is 1
year of life or 1 less stroke worth?),
cost-benefit analysis is used infrequently in the medical arena. When
a study measures health benefit in
disease-specific terms (eg, strokes
prevented), the method is referred
to generically as cost-effectiveness
analysis. Although measuring health
benefit in disease-specific terms may
be helpful in comparing interventions for a specific condition, it is less
useful for comparing interventions
across diseases. For example, it is un-
clear whether preventing 1 stroke at
a cost of $10 000 is better or worse
than preventing 1 hip fracture at a
cost of $5000.
To facilitate comparisons
across diseases, analysts often measure health benefit as the gain
in quality-adjusted life years
(QALYs).12,13 Quality-adjusted life
years are designed to capture the
effects of an intervention on both
length and quality of life. Specifically, time spent in less than ideal
health is adjusted downward. The
degree of adjustment is determined
by the utility for that health state.
If, for example, a patient with heart
failure equates 2 years of life at his
or her present health state with 1
year of life at ideal health, then the
utility for that individual’s present
health state is 0.5 (ie, 1 year of ideal
health is worth 2 years of present
health). In other words, each year
of life at the present health state is
equivalent to 0.5 QALY. The costutility ratio, defined as the cost
required to gain 1 QALY, permits
cost comparisons to be made across
a wide range of interventions and
diseases. Specific methods have
been developed for assessing utilities, and the reader is referred to
other sources for additional details
and examples.14
Although there are several
ways of categorizing costs, the total
costs associated with a specific
m e d ical illness or condition
include 3 major components:
direct costs, indirect costs, and
intangible costs.14,15 Direct costs
encompass the actual costs of services rendered, including hospitalization costs, diagnostic tests and
procedures, medications, office visits, and rehabilitation costs. Indirect costs include loss of income as
a result of illness, travel expenses,
and costs for specialized services,
such as meals-on-wheels and adult
day care. Intangible costs include
the nonquantifiable costs associated with physical and emotional
pain and suffering. Although some
cost-utility analyses attempt to
include these factors in assessing
health benefit, most published cost
analyses include only direct costs,
and these are often limited to hospital costs or some other component of the total direct costs.
Cost vs Charge
The term cost refers to the actual or
true costs associated with providing a service. Unfortunately, the
true costs are often difficult to
determine, since they may include
such diverse resources as personnel, space, equipment, depreciation, and shared goods (eg, electricity and telephone). For this
reason, charges are often used as a
surrogate for costs. However,
charges do not necessarily reflect
true costs in any consistent fashion. For example, the charge for
performing a specific procedure is
often fixed, whereas the cost is
dependent on several factors,
including procedure volume (ie,
the cost per case is lower if 10
echocardiograms are performed
per day than if only 1 is performed). In an effort to overcome
this and other limitations, a costto-charge ratio is often calculated.16
This ratio is based on estimated
true costs and charges at a given
institution, and it is therefore
facility-specific. On the other hand,
in most cases the cost-to-charge
ratio is not based on specific procedures or diagnoses, and for this
reason it may not provide a valid
method for estimating costs.
Another approach to estimating costs is through reimbursement
or collections data. Under the Medicare Prospective Payment System,
hospitals receive a predetermined
amount of money for each hospitalization, and this amount is based primarily on the discharge diagnosis category (diagnosis related group
[DRG]). The reimbursement schedule, which is designed to reflect average costs adjusted for region and comorbidity, provides a simple method
for gauging hospitalization costs. Unfortunately, DRG reimbursement may
not reflect actual costs at a given institution or for an individual patient.
Discounting
In performing cost-effectiveness
analyses, it is often important to determine the time frame during which
costs and benefits accrue, since the
current value of benefits to be
achieved in the future is less than the
value of the same benefits achieved
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Sensitivity Analysis
In most cost-effectiveness analyses,
a series of assumptions are made concerning both costs and outcomes. For
example, the average cost of intervention X may be estimated at
$10 000, the health benefit may be assumed to be the prevention of 1
stroke for each 50 patients treated,
and the risk of major complications
may be estimated at 2%. Not surprisingly, the calculated incremental costeffectiveness ratio may vary considerably depending on the validity of
the baseline assumptions. Sensitivity analysis assesses the impact on the
cost-effectiveness ratio of varying the
baseline assumptions across a range
of clinically plausible values.9,10 Sensitivity analysis thus provides insight into the stability of the costeffectiveness ratio, identifies those
baseline assumptions that have the
greatest impact on overall costs, and
defines boundaries beyond which a
specific intervention may no longer
be cost-effective (eg, if the reduction in mortality is less than 10% or
if the complication rate exceeds 5%).
Interpretation of
Cost-effectiveness Analyses
In comparing 2 treatment strategies
using cost-effectiveness analysis, 1 of
4 results may occur (Figure). The
first situation (quadrant I) occurs
when the new intervention is both
more effective (eg, saves more lives,
prevents more strokes) and less expensive than standard treatment. In
this case, the new intervention is said
to dominate, and it is clearly costeffective. In a second scenario, the
new intervention may be both less effective and more costly than standard treatment (quadrant III). This
is the opposite of the first possibility, and in this case the standard treatment dominates. When 1 intervention dominates another, interpreting
the analysis is straightforward. Unfortunately, such dominance occurs
infrequently in the clinical setting.
The third possibility occurs
when the intervention is less effective and also less costly (quadrant II).
This possibility presents a dilemma,
since there may be situations where
the less effective and less expensive
treatment is actually more costeffective. Depending on resource
availability, the less costly therapy
may represent the best clinical option. The fourth possibility (quadrant IV) occurs when the new therapy
is both more effective and more expensive (eg, tissue plasminogen activator compared with streptokinase
for acute myocardial infarction). In
this last situation, which occurs commonly, as well as in scenario 3, the
cost-effectiveness ratio can provide
guidance as to the relative merits of
the 2 interventions. Specifically, the
incremental cost-effectiveness ratio
(dollars per year of life gained) or the
incremental cost-utility ratio (dollars per QALY gained) expresses the
relative efficiency of the 2 interventions in producing health benefits.
What constitutes a cost-effective intervention? Clearly, any
new treatment that reduces costs
without compromising efficacy is
cost-saving and therefore costeffective. Renal dialysis is a common benchmark used to assess the
cost-effectiveness of interventions
that are both more effective and
more costly. Renal dialysis is estimated to cost approximately $40 000
for each year of life gained. Alternatively, Goldman et al17 have suggested that an incremental costeffectiveness ratio of less than
$20 000 per QALY is very attractive, a ratio of $20 000 to $60 000 per
QALY is acceptable, a ratio of
$60 000 to $100 000 per QALY is
higher than currently accepted standards, and a ratio in excess of
$100 000 per QALY is unattractive.
However, since the incremental costeffectiveness ratio involves a tradeoff
between dollars spent and health
benefits gained, the ranges suggested by Goldman et al (or by any
arbitrary set of thresholds used for
decision making) reflect society’s
current willingness to pay for a specific benefit, and these ranges are
therefore a matter of public policy
+
III
IV
Effectiveness
–
II
+
I
–
Possible outcomes of cost-effectiveness
analysis (explained in the “Interpretation of
Cost-effectiveness Analyses” section).
rather than a scientifically based assessment of true cost-effectiveness.
In evaluating the results of costeffectiveness analysis, several additional factors should be considered.
Did the analysis compare 2 potentially effective interventions, or was
a single intervention compared with
placebo? It is often easier to demonstrate cost-effectiveness when the new
treatment is compared with no
therapy. Was the analysis based on
costs or charges? Because charges
typically exceed costs, analyses based
on charges will tend to overestimate
the true cost-effectiveness ratio. Was
the population studied representative of clinical practice? If the study
sample was highly selected, the results of the analysis may not be applicable to the general population.
What was the time horizon for the
analysis? Although data are often
available only for the near term,
health benefits may be long-lasting,
and this should be factored into the
analysis. Were costs and health benefits appropriately discounted? If not,
the true cost-effectiveness could be
either overestimated or underestimated. How were the benefits measured, and was quality of life taken
into consideration? Did the study
evaluate all costs, or was it limited to
direct costs or to an even smaller
component of total costs (eg, hospitalization costs)? The nature of the
cost analysis can have a profound effect on the study’s implications. For
example, a new intervention may
have a favorable effect on stroke survival without increasing hospital
costs, and such an intervention would
therefore appear to be cost-effective. However, if neurological func-
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Cost
today. Thus, an individual would be
willing to pay more today to prevent a stroke tomorrow than to prevent a stroke 10 years from now.
Cost-effectiveness analysis accounts for the time value of both
money and health benefits by discounting future value, usually at a
fixed rate (eg, 3%/year).9,10
tion is not improved, and if survivors require prolonged rehabilitation
and nursing home care, the overall
cost-effectiveness of the intervention may be greatly compromised.
Limitations
Although cost-effectiveness analysis
provides a useful tool for evaluating
therapeutic strategies and developing treatment and reimbursement
policies, certain methodological limitations must be recognized. First,
well-designed randomized controlled trials with prospectively collected cost data that directly measure the effect of a specific
intervention on an identified outcome are exceedingly uncommon.
This lack of direct evidence mandates the use of sophisticated modeling techniques that often combine
data from a variety of sources and rely
on expert judgment to estimate clinical outcomes and related costs. These
estimates, which are often based on
a series of assumptions, may or may
not accurately reflect true costs and
benefits. Although sensitivity analysis provides a method for evaluating
the robustness of the model, the quantitative outcome of the analysis may
nonetheless communicate a level of
precision that is unwarranted.
A second limitation relates to
the generalizability of a specific
analysis to routine clinical practice. Cost-effectiveness analyses are
often based on data from clinical trials that may involve a highly selected patient population treated in
a specific practice environment (eg,
an academic medical center) for a
fixed period. Clearly, the results of
these analyses may not be directly
applicable to other patient populations, practice settings, or time horizons. In addition, analysts may use
different methods and assumptions in developing cost-effectiveness models, and these differences
may substantially influence the results. For these reasons, care should
be taken both in comparing the results of different cost-effectiveness
analyses and in applying the results to clinical practice.
A third limitation concerns the
inability to measure intangible costs
and the related difficulty of accurately quantifying quality of life. Both
of these factors may serve to limit the
validity of cost-effectiveness analyses in general and cost-utility analyses in particular.
Despite these limitations, costeffectiveness analysis offers a unique
means to generate insights into the
costs and benefits associated with
therapeutic interventions, for which
the outcomes are often complex, dynamic, and uncertain.
Clinical Implications
Cost-effectiveness analysis may be
used to compare costs associated
with selected interventions when total resources are limited. For example, in choosing between 2 new
and unrelated programs, both of
which would cost $100 000 per year
to operate, policy makers would
have an apparently easy choice if 1
program spent $20 000 per QALY
gained, while the other spent
$200 000 per QALY gained. Without a cost-utility analysis, the relative clinical merits of the 2 programs may be less apparent.
At the level of the individual
practitioner, however, the situation
is much more complex. Physicians
are appropriately concerned with providing each individual patient with
the best possible care. Although cost
may come into play, it is not and
should not be the overriding concern.
It cannot be expected, for example,
that physician A will voluntarily withhold treatment X from a given patient
becauseofthetheoreticalconcernthat
administering such treatment will
mean that physician B will not be able
to give treatment Y (ie, a more costeffective therapy) to another patient.
Despite these difficulties, costeffectiveness analysis is increasingly
being used to guide policy and influence medical decision making. It is
therefore appropriate for physicians
to have a working knowledge of costeffectiveness analysis and its pitfalls.
TREATMENT OPTIONS
Angiotensin Converting
Enzyme Inhibitors
Angiotensin converting enzyme
(ACE) inhibitors have become the
cornerstone of therapy in patients
with significant left ventricu-
lar systolic dysfunction, as evidenced by a left ventricular ejection
fraction of less than 0.40 whether or
not overt heart failure is present.18 As
shown in Table 1, several studies
have now examined the cost implications of ACE inhibitor therapy.19-22
In 1994, Paul et al19 developed
a decision-analytic model to evaluate the cost-effectiveness of enalapril maleate therapy and of the combination of hydralazine hydrochloride
and isosorbide dinitrate in comparison with standard therapy with digoxin and diuretics. Direct costs were
calculated as the sum of hospitalization costs and medication costs.
Hospitalization costs were derived using a detailed cost-accounting procedure incorporating the cost-tocharge ratio, indirect costs, and the
costs of ancillary services. The costs
used in this analysis were thought to
reflect actual costs incurred by the
hospital. Using this method, the average cost per hospitalization was
estimated as $6750 in 1992 US
dollars. Medication costs were determined by surveying 10 retail pharmacies and averaging the results. The
average cost for enalapril maleate
therapy (20 mg/d) was $959 per year,
and the cost of hydralazine hydrochloride (300 mg/d) plus isosorbide
dinitrate (160 mg/d) therapy was
$437 per year (both in 1992 US dollars). Efficacy data for the 2 treatments were derived from the first and
second Veterans Administration
Heart Failure Trials and from the
Studies of Left Ventricular Dysfunction treatment trial.26-28 The model assumed that treatment was continued for 10 years and that the
beneficial effects were linear over
time. Both costs and benefits were
discounted at the rate of 5% per year.
Sensitivity analysis was performed to
examine the impact of variations in
model assumptions on incremental
cost-effectiveness.
In the base-case scenario (ie,
prior to performing sensitivity analysis), the principal findings of the
study were that, relative to standard therapy, the incremental costeffectiveness ratio for enalapril
therapy was $9700 per year of life
saved, while the ratio for hydralazine-isosorbide therapy was $5600
per year of life saved.19 These estimates are well below the cost-
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Table 1. Cost-effectiveness of Pharmacological Agents for the Treatment of Heart Failure*
Data
Extraction
Source, y
19
Therapeutic
Agent(s)
Clinical Outcomes
Cost Outcomes
Comments
Paul et al,
1994
V-HeFT I
V-HeFT II
SOLVD
Enalapril maleate,
hydralazine
HCl/isosorbide
dinitrate
V-HeFT I: 34% reduction in
mortality with
hydralazine/isosorbide
V-HeFT II: 28% reduction in
mortality with enalapril
SOLVD: 16% reduction in
mortality with enalapril,
fewer HF admissions
Compared with standard therapy:
hydralazine/isosorbide:
$5600/y of life saved,
enalapril: $9700/y of life saved
Assumptions:
therapy continued for 10 y,
benefits linear over time,
discount rate: 5%/y, estimated
cost for HF admissions:
$6750; sensitivity analysis:
little effect
Butler and
Fletcher,20
1996
SOLVD
Enalapril
16% Mortality reduction,
increased survival by
1.68-1.80 mo, decreased
HF admissions
Net savings of $171-$252/patient
treated with enalapril;
worst-case scenario:
$21 735/y of life saved
Assumptions:
4-y treatment period,
$6224/HF admission,
discount rate: 5%/y
Kleber,21 1994
Munich MHFT
Captopril
59% Reduction in HF progression
Total costs “almost identical”
with captopril vs placebo
Modest increase in cost for
stable patients, cost-saving for
patients with progressive HF
Tsevat et al,22
1995
SAVE
Captopril
19% Mortality reduction, 22%
reduction in HF admissions,
25% reduction in MIs
Cost per QALY ranged from
$60 800 to $3700 for patients
aged 50-80 y if benefit ceased
after 4 y
If benefit persists beyond 4 y,
CE ratio improves in younger
patients; sensitivity analysis:
CE ratio always favorable for
patients aged 60-80 y
Ward et al,23
1995
PROVED
RADIANCE
Digoxin
PROVED: 50% reduction in HF
exacerbations
RADIANCE: 77% reduction in HF
exacerbations
Continuation of digoxin therapy
saved $338/patient
Withdrawal studies; sensitivity
analysis: digoxin is
cost-saving if incidence of
toxic effects ,33%/y
Delea et al,24
1999
US Carvedilol
Carvedilol
Heart Failure
Trials
65% Mortality reduction,
27% reduction in CV
admissions
Incremental cost-effectiveness
ratio range: $12 800 to
$29 500/life-year saved
Projected lifetime costs based on
limited or sustained benefits of
therapy
55% Reduction in admissions,
72% reduction in hospital days
86% Reduction in inpatient
expenditures
Not a formal cost analysis, effect
on mortality unknown
Marius-Nunez Michael Reese
et al,25 1996
Hospital,
Chicago, Ill
Milrinone,
dobutamine
*V-HeFT indicates Veterans Administration Heart Failure Trial; SOLVD, Studies of Left Ventricular Dysfunction treatment trial; HCl, hydrochloride; HF, heart
failure; MHFT, Mild Heart Failure Trial; SAVE, Survival and Ventricular Enlargement trial; MIs, myocardial infarctions; QALY, quality-adjusted life year;
CE, cost-effectiveness; PROVED, Prospective Randomized Study of Ventricular Failure and Efficacy of Digoxin trial; RADIANCE, Randomized Assessment
of Digoxin and Inhibitors of Angiotensin Converting Enzyme trial; CV, cardiovascular; and ICU, intensive care unit.
effectiveness ratio of renal dialysis,
and both fall within the attractive
category of Goldman et al.17 In addition, wide variations in the baseline assumptions had little effect on
the cost analysis.
In another analysis based on
data from the Studies of Left Ventricular Dysfunction treatment trial,
Butler and Fletcher20 estimated the
cost-effectiveness ratio of enalapril
therapy administered over a 4-year
period. As in the analysis of Paul et
al, direct costs were calculated as the
sum of drug costs and hospitalization costs. However, unlike the analysis of Paul et al, Butler and Fletcher
estimated drug costs as a function of
the proportion of patients remaining on active therapy during the
4-year follow-up period. In addition, the costs associated with moni-
toring enalapril therapy (eg, checking serum electrolyte levels and renal
function), obtaining additional consultations, and, in a small percentage of cases, the need for hospitalization were incorporated into the
model. Furthermore, the added costs
associated with providing standard
care during the period of increased
survival (estimated at 1.68-1.80
months per patient) in patients who
were treated with enalapril was also
included in the model. Hospital costs
were estimated from DRG data (eg,
$6224 for DRG 127, heart failure),
adjusting for differences in hospital
costs associated with fatal vs nonfatal outcomes. The authors also adjusted for cost differences associated with death in or out of the
hospital. Cost data were reported undiscounted as well as discounted at
a rate of 5% per year, and extensive
sensitivity analyses were performed.
Overall, the authors estimated
that the average additional costs of
enalapril therapy were $1892 over 4
years. These costs were offset by projected cost savings of $2063 to $2144
per patient as a result of fewer hospitalizations, yielding net savings of
$171 to $252 per patient (ie, enalapril treatment dominated).20 In the
sensitivity analysis, the worst-case
scenario cost-effectiveness ratio was
$21 737 per year of life saved. Thus,
this analysis also supports the view
that ACE inhibitor therapy is highly
cost-effective; a similar analysis performed in the United Kingdom
reached the same conclusions.29
In the Munich Mild Heart Failure Trial, 170 patients with New York
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Heart Association class II status heart
failure and a left ventricular ejection fraction of 0.35 or less were randomized to receive captopril therapy
(25 mg twice daily) or to receive placebo and were followed up for an average of 2.7 years.30 The study’s major finding was that the rate of heart
failure progression was reduced from
30% in the control group to 12% in
the captopril therapy group (P = .01).
In a subgroup of 140 patients, the effects of captopril therapy on inpatient and outpatient costs for heart
failure treatment were examined over
a 15-month period.21 Among patients who did not experience progressive heart failure during followup, total costs were higher in patients
who were treated with captopril than
in those who received placebo (303
vs 218 Deutschmarks per patient per
month), primarily as a result of the
added cost of drug therapy. In contrast, captopril therapy was costsaving (ie, dominant) in patients who
developed progressive heart failure
(643 vs 737 Deutschmarks per patient per month). When these data
were extrapolated to the total population and trial period, total cost outlays were “almost identical” in the 2
treatment arms, and the investigators concluded that treatment with
ACE inhibitors did not impose “a further economic burden.”21
In another study, Tsevat et al22
used a decision-analytic model to
evaluate the cost-effectiveness of captopril therapy in patients with a left
ventricular ejection fraction of less
than 0.40 following acute myocardial infarction. Data on costs, healthrelated quality of life, and 4-year survival were obtained directly from the
Survival and Ventricular Enlargement (SAVE) trial.31 Since there was
an interaction between age and survival benefit in the SAVE trial (older
patients obtained greater benefit),
separate cost-effectiveness models
were developed for patients aged 50,
60, 70, or 80 years at the time of presentation. In addition, separate models were constructed assuming that
the benefits of captopril therapy persisted beyond 4 years, or that they
were limited to the first 4 years of
therapy. (In the SAVE study, KaplanMeier curves for cardiovascular mortality, recurrent myocardial infarction, and incident heart failure
continued to diverge up to 4 years,
but data beyond 4 years are unavailable.) To translate the survival benefits associated with captopril therapy
into QALYs, utility rates were determined in a subgroup of 82 patients
using the time trade-off method, and
these data were extrapolated to the
entire study population. Cost estimates were based on actual resource utilization, with the DRG reimbursement rate used to estimate
hospital costs and the resourcebased relative value system used to
calculate physician fees. Medication
costs were based on the wholesale acquisition cost with the addition of a
monthly dispensing fee. Outpatient
clinic costs were adjusted to reflect
usual practice, and the costs of outpatient diagnostic tests were assumed to be equal in both groups. All
costs were converted to 1991 US dollars and discounted at a rate of 5% per
year. Sensitivity analysis was performed over a wide range of variance in the baseline assumptions.
The cost of captopril therapy
was estimated at $631 per year. Costs
for other cardiac medications and
outpatient care were similar in the
2 groups. Hospitalization costs were
lower with captopril therapy during both the first and second years
of treatment ($5950 vs $8687 for the
first year, $1958 vs $2298 for the second year). Utility rates were slightly
but not significantly lower in the
captopril therapy group (0.88 vs
0.89). In the baseline limitedbenefit cost-utility model, the incremental cost per QALY ranged from
$60 800 for patients aged 50 years
to $3600 for patients aged 80 years.22
In the persistent-benefit model, the
estimated cost per QALY ranged
from $10 400 for patients aged 50
years to $3700 for patients aged 80
years. In the worst-case scenario sensitivity analysis, captopril therapy remained cost-effective for patients
aged 60, 70, and 80 years ($29 200,
$13 700, and $8700 per QALY, respectively), but was unattractive for
patients aged 50 years ($217 600 per
QALY).
In summary, multiple analyses
have indicated that ACE inhibitor
therapy in patients with left ventricular systolic dysfunction is almost always cost-effective and frequently
cost-saving.
Other Pharmacological Agents
The recently completed Digitalis Investigation Group study found that
digitalis reduced all-cause hospital admissions by 6% and reduced the composite end point of death or hospitalization caused by worsening heart
failure by 25%.32 Unfortunately, no
associated cost analysis has been published. However, Ward et al23 used a
decision-analytic model to estimate
the costs associated with withdrawal of digoxin therapy in patients with New York Heart Association class II or III status heart failure,
an ejection fraction less than 0.35,
and sinus rhythm (Table 1). Outcome data were derived from the Prospective Randomized Study of Ventricular Failure and Efficacy of
Digoxin (PROVED) and the Randomized Assessment of Digoxin and
Inhibitors of Angiotensin Converting Enzyme (RADIANCE) trials.33,34 In the PROVED trial, which
enrolled patients not receiving concomitant ACE inhibitor therapy, the
relative risk of developing an exacerbation of heart failure within 12
weeks of randomization was 0.50 in
patients continuing to receive digoxin therapy compared with those
from whom digoxin therapy was
withdrawn.33 In the RADIANCE trial,
which enrolled patients who were
also receiving an ACE inhibitor, the
relative risk of developing heart failure within 12 weeks was 0.23 in patients continuing to receive digoxin
therapy compared with those no
longer receiving treatment.34
Cost estimates in the PROVED
and RADIANCE trials were based on
Health Care Finance Administration data and local practices using the
cost-to-charge ratio; they included the
costs of heart failure–related office
visits, emergency department visits,
and hospitalizations, as well as the
costs of digoxin therapy, serum digoxin monitoring, and the costs of
treating digoxin toxicity. All costs
were converted to 1991 US dollars
and a detailed sensitivity analysis was
performed. Compared with digoxin
therapy withdrawal, continuation of
digoxin therapy was associated with
a net annual cost savings of $338 per
patient (range, $88-$685 per patient per year). In the sensitivity
analysis, maintenance of digoxin
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therapy was cost-saving as long as the
annual incidence of digoxin toxicity
was less than 33%.23 Projecting the
results of this analysis to the estimated 1.2 million adults in the United
States with stable heart failure, the authors estimated that digoxin therapy
saves $406 million annually in total
heart failure costs (range, $106$822 million). Importantly, digoxin
therapy was cost-saving both in patients treated with an ACE inhibitor
and in those not taking an ACE inhibitor.23
The principal limitation of this
analysis relates to the overall design
of the PROVED and RADIANCE trials, both of which were withdrawal
studies.33,34 The implications of these
findings for patients not previously
treated with digoxin therapy are thus
unclear. In addition, generalizing the
findings to the larger US population
is rather speculative. Nonetheless,
since digoxin is an inexpensive
therapy that significantly reduces
both all-cause hospitalizations and
heart failure hospitalizations,32 it is
quite likely that digoxin therapy is
cost-effective and possibly costsaving. Clearly, the analysis from
the PROVED and RADIANCE trials
supports this hypothesis.
Three large, prospective, randomized studies have now demonstrated the beneficial effects of b-adrenergic blocking agents for the
treatment of heart failure, and a cost
analysis based on data from the US
Carvedilol Heart Failure Trials Program found that carvedilol therapy is
also cost-effective (Table 1).24 Using
a Markov model to project life
expectancy and lifetime medical
costs, the addition of carvedilol to
conventional heart failure therapy
was associated with an incremental
cost-effectiveness ratio of $29 477 per
life-year saved in a limited benefits
scenario and $12 799 per life-year
saved in an extended benefits model.
In both of these models, the benefits
of carvedilol therapy, in terms of reducing hospitalizations and mortality,35 were assumed to persist for 6
months after the end of the carvedilol therapy trial and then to either
end abruptly (limited benefit) or taper
gradually over a period of 3 years (extended benefit). Since the extended
benefit scenario is more likely to reflect actual practice, it appears that
carvedilol therapy is cost-effective, although probably not cost-saving.
An additional therapeutic option for patients with advanced heart
failure is intermittent inotropic
therapy. In a retrospective observational study, Marius-Nunez et al25
evaluated the effects of intermittent
outpatient treatment with milrinone
therapy (n = 32) or dobutamine
therapy (n = 4) in patients with stable
New York Heart Association class III
or IV status heart failure (Table 1).
Compared with the period prior to
treatment, outpatient inotropic
therapy was associated with a 55% reduction in hospital admissions, a 72%
reduction in hospital days, and a 52%
reduction in emergency department
visits. Although a formal cost analysis was not performed, the authors estimated that intermittent inotropic
therapy was associated with an 86%
reduction in inpatient expenditures.25 This study is limited by its before-after design, the fact that certain patients were excluded from the
analysis, the failure to account for the
cost of outpatient therapy, and uncertainty about the long-term effects
of inotropic therapy on clinical outcomes. Future studies that address
these limitations may demonstrate
that intermittent inotropic therapy is
a cost-effective approach to treating
a highly selected group of patients
with end-stage heart failure.
Nonpharmacological Therapies
Heart failure often occurs in the setting of multiple comorbid illnesses,
such as hypertension, coronary artery disease, diabetes mellitus, renal
insufficiency, and chronic lung disease. In addition, heart failure management is often complicated by behavioral (eg, noncompliance),
psychological (eg, depression), social (eg, isolation, especially in the elderly), and economic (eg, inability to
pay for medications) factors, and
these factors frequently contribute to
heart failure exacerbations.36,37 For
these reasons, many centers are now
employing an interdisciplinary approach to heart failure management, and several studies have now
documented improvements in clinical outcomes (Table 2).38-48 Although the composition of an interdisciplinary team may vary from
center to center, the team is usually
directed by a nurse-coordinator or
case manager, with additional support provided by a dietitian, social
worker, pharmacist, and/or home
health specialist, in addition to the
primary care physician and consultant cardiologist.
While all of the studies listed
in the first section of Table 2 reported a favorable effect on clinical
outcomes, only 4 reported cost
data.38,40,43,44 In 1983, Cintron et al38
evaluated the effects of a nursepractitioner–based clinic on hospital admissions, total hospital days,
and medical costs in 15 patients with
chronic heart failure. Data from an
average period of 24 months prior
to implementation of the clinic were
compared with data for an equivalent period after implementation.
Medical costs were calculated as the
sum of total inpatient hospital days
at $165 per diem plus total outpatient visits at $61 per visit. The inpatient per diem cost estimate was
obtained from the hospital’s financial division; the outpatient visit
costs reflected average costs for all
services, including laboratory tests,
medications, and transportation.
Prior to implementing the study
intervention, the annual number of
hospitalizations was 1.8 ± 0.2 per patient and total hospital days averaged 62 ± 14 per year (mean ± SD).
Following the intervention, the annual number of hospitalizations declined 60% to 0.7 ± 0.2 per patient and
hospital days fell by 85% to an average of 9 ± 4 per patient (P,.001 for
both).38 As a result, average annual inpatient costs decreased by $8745 per
patient. Patients averaged 18 outpatient clinic visits per year after intervention, resulting in an average increase in outpatient costs of $736 per
patient. Thus, there was a net mean
cost savings of $8009 per patient per
year.38 Limitations of this study include the nonrandomized beforeafter study design and the very small
number of patients. In addition, data
on mortality and quality of life were
not reported. Also, it is not clear
whether the cost of the nursepractitioner’s salary was included in
the analysis. Nonetheless, the data
clearly suggest that the intervention
improved outcomes and reduced
costs and was therefore dominant.
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Table 2. Studies of Multidisciplinary Heart Failure Management*
Source, y
Study Design
No. of
Patients
Intervention
Duration of
Follow-up
Results
Comments
Studies Without a Pharmacological Component
Cintron et al,38
1983
Observational
preintervention and
postintervention
15
Nurse-practitioner–based
24 mo†
clinic with physician referral
as needed, average of 18
clinic visits per year
61% Reduction in
hospitalizations, 85%
reduction in hospital days,
cost reduction of
$8000/patient per year
Mean age, 65 y; NYHA
class III-IV; improved
patient satisfaction
Rich et al,39
1993
Randomized pilot
study
98
Nurse-directed team with
patient education, dietary
counseling, social services,
home care, telephone
follow-up
90 d
27% Reduction in readmissions,
25% reduction in hospital
days
All patients aged .70 y;
mean NYHA class, 2.8
Lasater,40 1996
Observational
preintervention and
postintervention
80
Nurse-managed heart failure
clinic with access to
physician, dietitian, and
social worker
6 mo
14% Reduction in
hospitalizations, 22%
reduction in length of stay,
hospital costs reduced by
$500/patient
No information provided
on patient population
Kostis et al,41
1994
Randomized parallel
groups
20
Exercise, cognitive therapy,
12 wk
stress management, dietary
counseling
Improved exercise tolerance;
reduced anxiety, depression;
enhanced weight loss
Age range, 54-77 y;
digoxin group and
placebo group as
controls
Kornowski et
al,42 1995
Observational
preintervention and
postintervention
42
Intensive home care
1y
surveillance by internist and
paramedical team, at least
1 visit per week
62% Reduction in
hospitalizations, 77%
reduction in hospital days,
72% reduction in CV
admissions, improved ability
to perform activities of daily
living
Mean age, 78 y; NYHA
class III-IV
Rich et al,43
1995
Randomized clinical
trial
282
Nurse-directed team with
patient education, dietary
counseling, social services,
home care, telephone
follow-up
90 d
44% Reduction in readmissions;
56% reduction in HF
admissions, improved quality
of life, improved compliance,
cost reduction of $460/patient
Mean age, 79; high-risk
population; benefits
persisted up to 1 y
Stewart et al,44
1999
Randomized clinical
trial
97
Single home visit by nurse
and pharmacist 1 wk
after discharge
18 mo
50% Reduction in admissions,
46% reduction in mortality,
52% reduction in hospital
costs
Mean age, 75 y; NYHA
class II-III; high risk
population
Dennis et al,45
1996
Retrospective chart
review
24
Home health nurse, teaching,
clinical assessments
1y
Frequency and intensity of visits
inversely correlated with
readmissions
Age, other demographic
data not specified
Martens and
Mellor,46
1997
Retrospective chart
review
924
Home health nurse, teaching,
clinical assessments
90 d
36% Fewer readmissions in
patients receiving home care
Mean age, 71 y
West et al,47
1997
Observational
preintervention and
postintervention
51
Physician-supervised,
138 ± 44 d‡ 74% Reduction in
Mean age, 66 y; NYHA
nurse-mediated,
hospitalizations; 87%
class I-II, 60%, class
home-based system with
reduction in HF admissions;
III-IV, 40%; initial
frequent telephone contacts
fewer office and ED visits;
clinic visit,
targeting medication
improved symptoms, quality
subsequent follow-up
dosing, compliance,
of life, exercise tolerance;
by telephone
activities, symptom status
improved ACE inhibitor dosing
and salt restriction
Fonarow et al,48 Observational
1997
preintervention and
postintervention
214
Comprehensive management
by HF/transplant team,
including diet, exercise,
teaching, medications
Studies With a Pharmacological Component
6 mo
35% Reduction in
hospitalizations, improved
NYHA class and exercise
tolerance, improved
medication dosing, cost
reduction of $9800/patient
Mean age, 52 y; NYHA
class III-IV
*NYHA indicates New York Heart Association; CV, cardiovascular; HF, heart failure; ED, emergency department; ACE, angiotensin-converting enzyme.
†Mean.
‡Mean ± SD.
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Table 3. Cost of Multidisciplinary Heart Failure Management
During 90 Days of Follow-up*
Cost, $
Cost Domain
Intervention
Caregivers
Other medical care
Readmissions
Total
Control
Group
Treatment
Group
Difference
NA
828
1211
3236
5275
216
1164
1257
2178
4815
+216
+336
+46
−1058†
−460
*Average cost per patient. NA indicates not applicable.
†P=.03.
In a second study, Lasater40 analyzed the effects of a nurse-managed
heart failure clinic on hospital readmissions, length of stay, and hospital charges in 80 patients with chronic
heart failure. In the 6-month period
prior to starting the clinic, the hospital readmission rate was 25.6% and
the average hospital length of stay was
7.3 days. During the 6 months after
the clinic was started, the readmission rate declined to 21.9% and the
average length of stay decreased to 5.7
days (P,.05 for both). Hospital
charges were reduced from $6898 per
patient before intervention to $6405
after intervention, for net savings of
$493 per patient.40 This study is limited by its nonrandomized design as
well as by its failure to account for the
cost of the intervention. In addition,
it is unknown to what extent the hospital charges reflected the actual costs.
Despite these problems, the study
lends support to the use of a nursebased clinic as an effective and possibly cost-effective approach to heart
failure management.
In the largest study published to
date, Rich and colleagues43 randomized 282 patients 70 years of age or
older who were hospitalized with
heart failure to conventional, physician-directed care or to conventional care supplemented by a nursedirected interdisciplinary team. The
intervention included intensive patient education, dietary consultation, social service evaluation, medication review, and close follow-up
after discharge by a home health specialist and study nurse. All patients
were evaluated for 90 days, during
which all-cause readmissions were reduced by 44% (P = .02), heart failure
readmissions were reduced by 56%
(P = .04), and the number of pa-
tients experiencing multiple readmissions was reduced by 61% (P = .01).
Patients in the intervention group also
experienced an improved quality of
life and greater compliance with
medications and diet than patients in
the usual care group.49
During the final year of the
study (1994), the authors prospectively collected detailed cost data for
57 patients through the use of cost
logs and frequent patient interviews.43 Cost data were analyzed in
4 domains, including readmission
costs (based on DRG reimbursement), other direct medical costs (eg,
outpatient services, medications),
caregiver costs (ie, time spent by family and friends caring for the patient, prorated at $6/hour), and costs
associated with the intervention itself. As shown in Table 3, the combined costs of the intervention, caregiver time, and other medical services
were $598 higher per patient in the
treatment group (P, not significant). Conversely, readmission costs
per patient were $1058 lower in the
treatment group (P = .03), yielding
a net cost savings of $460 per
patient.43 Thus, from the cost-effectiveness perspective, the intervention dominated. The principal limitations of this study were that the
patient population was highly selected (only 21% of elderly patients
with heart failure were enrolled), and
the index event for all patients was
acute heart failure exacerbation. The
generalizability of these findings to
other populations and to the outpatient setting is therefore unknown.
More recently, Stewart et al44 reported the results of a randomized
trial involving 97 patients with heart
failure with an average age of 75
years. Patients received usual care af-
ter discharge (n = 48) or usual care
supplemented by the study intervention (n = 49), which included predischarge teaching by a study nurse and
a single home visit by a nurse and a
pharmacist 1 week after discharge.
The purpose of the home visit was to
assess compliance and clinical status, and subsequent referrals were
made to the primary care physician
and a local pharmacist as needed. Patients were evaluated for 18 months,
during which the intervention group
experienced 50% fewer readmissions. Mean hospital costs per patient were 52% lower in this intervention group ($5100 vs $10 600 in
Australian dollars), and the cost of the
intervention was estimated at $190
per patient (Australian dollars).44
In summary, although additional study is needed, currently
available data strongly suggest that
an interdisciplinary, nonpharmacological approach to heart failure
management can be highly costeffective, particularly in patients at
higher risk who have multiple comorbid conditions and/or other barriers that may interfere with their
ability to comply with treatment.
Multimodality Therapy
Two recent studies used an interdisciplinary approach combining nonpharmacological measures with efforts to maximize medical therapy
(Table 2).47,48 In the first study, West
and colleagues47 evaluated 51 patients
using a before-after study design and
reported that a physician-supervised,
nurse-mediated, home-based system
for heart failure management was associated with a 74% reduction in hospital admissions and a 53% reduction
in emergency department visits. Although no cost analysis was performed, the intervention costs were
likely modest, and the management
system was almost certainly costsaving.
In the second report, Fonarow
et al48 studied 214 patients referred
for possible heart transplantation.
Treatment included intensive patient education, optimization of the
medication regimen, and close follow-up after the initial assessment.
Compared with the 6-month period prior to referral, total hospital
admissions were reduced by 35%
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during the subsequent 6-month interval and functional status was also
improved. Hospital expenditures
prior to referral were estimated based
on published cost data, and hospital costs after referral were collected prospectively using the hospital’s accounting system and a costaveraging procedure. The cost of the
nurse specialist, including salary and
benefits during the 6-month follow-up period, was estimated at
$200 to $400 per patient. Not included in the analysis were the costs
of the transplant evaluation itself and
the cost of home health care; there
was also no sensitivity analysis. Under these assumptions, the authors
projected average savings of $9800
per patient during the 6-month period following referral to the heart
failure program.48
Not surprisingly, these 2 studies suggest that optimally costeffective management of patients
with heart failure may be best
achieved through a combined approach of interdisciplinary nonpharmacological measures and maximum medical therapy.
Surgical Options
A detailed review of the cost-effectiveness of various surgical options for
treating heart failure is beyond the
scope of this review. However, 2 separate analyses have projected that the
incremental cost-effectiveness ratio of
heart transplantation ranges from
$25 000 to $44 300 per year of life
gained.50,51 The cost-effectiveness of
newer treatments, such as portable left
ventricular assist devices, partial ventricular myectomy, and cardiomyoplasty, is currently unknown.
CONCLUSIONS
Current treatment options for the
management of heart failure include
nonpharmacological interventions, an
array of pharmacological agents, and,
in appropriately selected patients, orthotopic heart transplantation and
other surgical approaches. From the
cost perspective, the most effective interventions are those that reduce the
number of hospitalizations, length of
hospital stay, and/or number of intensive care unit days. Fortunately,
not only do many of the available
therapeutic modalities improve clinical outcomes (including a reduction
in hospital admissions), but they do
so at incremental cost-effectiveness ratios that are well within the desirable range,17 and that, in some cases,
provide a net cost savings. Within the
limitations of cost-effectiveness methodology, these data indicate that the
judicious use of medications, nonpharmacological interventions, and
surgical procedures not only leads to
the best clinical outcomes, but also
provides the most cost-effective approach to heart failure care.
Accepted for publication January 1,
1999.
We thank Marge Leaders for expert secretarial assistance in preparing the manuscript.
Corresponding author: Michael
W. Rich, MD, Barnes-Jewish Hospital, North Campus, 216 S Kingshighway, St Louis, MO 63110 (e-mail:
mrich@imgate.wustl.edu).
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