ORIGINAL INVESTIGATION
Cost-effectiveness of B-Type Natriuretic Peptide
Testing in Patients With Acute Dyspnea
Christian Mueller, MD; Kirsten Laule-Kilian, BSc; Christian Schindler, PhD; Theresia Klima, MD; Barbara Frana, MD;
Daniel Rodriguez, MD; André Scholer, PhD; Michael Christ, MD; André P. Perruchoud, MD
Background: B-type natriuretic peptide (BNP) is a quantitative marker of heart failure that seems to be helpful
in its diagnosis.
Methods: We performed a prospective randomized study
(B-Type Natriuretic Peptide for Acute Shortness of Breath
Evaluation) including 452 patients who presented to the
emergency department with acute dyspnea to estimate
the long-term cost-effectiveness of BNP guidance. Participants were randomly assigned to a diagnostic strategy involving the measurement of BNP levels (n= 225)
or assessment in a standard manner (n= 227). Nonparametric bootstrapping was used to estimate the distribution of incremental costs and effects on the costeffectiveness plane during 180 days of follow-up.
tensive care, and total days in the hospital at 180 days
(median, 10 days [interquartile range, 2-24 days] in the
BNP group vs 14 days [interquartile range, 6-27 days]
in the control group; P=.005). At 180 days, all-cause mortality was 20% in the BNP group and 23% in the control
group (P=.42). Total treatment cost was significantly reduced in the BNP group ($7930 vs $10 503 in the control group; P=.004). Analysis of incremental 180-day costeffectiveness showed that BNP guidance resulted in lower
mortality and lower cost in 80.6%, in higher mortality
and lower cost in 19.3%, and in higher or lower mortality and higher cost in less than 0.1% each. Results were
robust to changes in most variables but sensitive to
changes in rehospitalization with BNP guidance.
Conclusion: Testing of BNP is cost-effective in patients
Results: Testing of BNP induced several important
with acute dyspnea.
changes in management of dyspnea, including a reduction in the initial hospital admission rate, the use of in-
Arch Intern Med. 2006;166:1081-1087
T
HE CLINICAL DIAGNOSIS OF
heart failure (HF) may be
difficult,1-4 particularly in
patients presenting with
acute dyspnea in the emergency department (ED). Clinical history,
physical examination, electrocardiography, and chest radiography may provide valuable clues as to whether HF is the
cause of acute dyspnea.1,2 However, after
review of this information, physicians are
left with considerable diagnostic uncertainty in up to 50% of patients.4-6 Misdiagnosis of HF can lead to morbidity and
increased resource utilization.
Author Affiliations:
Department of Internal
Medicine (Drs Mueller, Klima,
Frana, Rodriguez, Christ, and
Perruchoud and
Ms Laule-Kilian), Institute of
Social and Preventive Medicine
(Dr Schindler), and Department
of Laboratory Medicine
(Dr Scholer), University
Hospital, University of Basel,
Basel, Switzerland.
See also pages
1063 and 1073
METHODS
PATIENT POPULATION
Recently, B-type natriuretic peptide
(BNP) has been suggested to be helpful
in this setting. Levels of BNP are reliably elevated in the setting of HF and
significantly increase the accuracy of
the clinical evaluation.4-10 The randomized B-Type Natriuretic Peptide for
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1081
Acute Shortness of Breath Evaluation
(BASEL) study showed that more rapid
and more accurate diagnosis results in a
reduction in the rate of hospitalizations,
time to discharge, and initial treatment
cost.11 Therefore, BNP testing may confer improvements in both the costs and
the effectiveness of treatment of patients
with acute dyspnea. We planned and
prospectively performed long-term costeffectiveness analyses of BNP testing in
patients enrolled in the BASEL study.
The design and primary results of the BASEL
study have been previously reported.11,12 Briefly,
452 patients presenting to the ED with acute dyspnea were enrolled in this randomized, controlled single-blind trial. Exclusion criteria included trauma, severe renal disease, and
cardiogenic shock. Groups were assigned with
the use of a computer-generated randomization scheme in a 1:1 ratio without stratification. A total of 225 patients were randomly as-
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signed to be examined with a diagnostic strategy that included
rapid measurement of BNP levels, and 227 were assigned to be
examined with the conventional diagnostic strategy.
increased mortality, cost-effectiveness analysis was performed
at 180 days of follow-up.
COST-EFFECTIVENESS ANALYSIS
PROCEDURES
All patients underwent an initial clinical assessment that included clinical history taking, physical examination, electrocardiography, pulse oximetry, blood tests, and chest radiography. The study investigators neither were directly involved in
patient care nor had any influence on the decision to admit or
discharge patients. The study was carried out in accordance with
the principles of the Declaration of Helsinki and approved by
the local ethics committee. Written informed consent was obtained from all participating patients.
During the initial evaluation, venous blood was collected
in tubes containing potassium EDTA. The BNP was measured
with the use of a rapid fluorescence immunoassay (Biosite Inc,
San Diego, Calif ). In the BNP-guided group, the BNP level was
considered in the context of the clinical information obtained
and the physicians’ clinical impression.11,12 We used 2 BNP cutoff levels (rule out, 100 pg/mL; rule in, 500 pg/mL) to separate
HF from other causes of acute dyspnea. In patients with a BNP
level less than 100 pg/mL, HF was considered unlikely and alternative causes of dyspnea had to be pursued. In patients with
a BNP level greater than 500 pg/mL, HF was considered very
likely and rapid therapy with diuretics, nitroglycerin, and angiotensin-converting enzyme inhibitors was recommended. Patients in the control group were examined and treated according to the most recent clinical guidelines.1,2
SURVIVAL AND RESOURCE USE
We obtained data on survival from the time of randomization
to the end of study follow-up and on the use of specific health
care resources. Patients were contacted 6 months after the initial presentation by telephone interview. In addition, referring
physicians were contacted. The calculation of total days in the
hospital and total cost of treatment included all hospitalizations after the initial presentation to the ED. Because ratios of
costs to charges have not been defined for most of the services
and departments at our institution, hospital charges were used
as the most appropriate estimate of the true costs.13,14 To avoid
an imbalance due to differences in reimbursement or charges
associated with different types or classes of insurance, charges
were standardized according to the actual rates for patients with
general insurance who were living in Basel, Switzerland. Expenses for hospital care were primarily determined by the intensity of care and the length of stay. The following cost weights
applied: for the first 3 days in hospital, $575 per day; for every
additional day, $383; for outpatient visits, $286; for visits of
less than 24 hours but with stay overnight in the ED, $381; and
for every hour in the intensive care unit, $86. Total cost of treatment also included cost of cardiovascular and pulmonary medication calculated according to standard rates in Switzerland in
2003. Other medication was not included in this cost analysis
because differences would be more likely due to differences in
baseline medical conditions than related to BNP testing. For
the cost of BNP testing, the reimbursement amount for the measurement of BNP in Switzerland ($47) in 2002 was used. Because of the short follow-up period, cost during follow-up was
not deflated. All end points were assessed in a blinded fashion
by physicians who were not involved in patient care, with the
use of all medical records pertaining to each patient. To address the possibility that tailoring of resources may be costeffective initially but may result in large secondary costs due
to recurrent symptoms and hospitalizations or potentially even
Cost-effectiveness analysis evaluates and compares both costs
and effects of alternative therapies. We estimated effects (mean
mortality rate) and the mean cost per patient for the BNP and
control groups. Mean cost was calculated by multiplying each
resource use component by the unit cost and summing the results for each patient; we then calculated the mean across all
patients. Recent developments in economic methods emphasize the importance of quantifying uncertainty about the incremental cost-effectiveness ratio by examining the joint density of cost and effect differences.15-17 Nonparametric bootstrap
analysis was used to estimate 95% confidence intervals for differences in average costs and for the incremental costeffectiveness ratios presented (each of these simulations using
5000 bootstrap samples drawn from the original data set), and
also to assess the shape of the joint sampling distribution of
the differences in average individual costs and effects between
the 2 groups.15-17 Uncertainties surrounding costs, benefits, and
cost-effectiveness were represented by confidence ellipses in
the “cost-effectiveness plane.”15-17 The presentation of costeffectiveness results as cost-effectiveness ratios with 95% confidence interval is inappropriate, since confidence intervals of
costs (ie, the numerator of the cost-effectiveness ratio) and effects (ie, the denominator of the cost-effectiveness ratio) are
multiplied, and also insufficient, since the interpretation of costeffectiveness ratios depends on the quadrants of the costeffectiveness plane into which incremental costs and effects
fall.17-19 For example, in the assessment of a less efficient but
cheaper new treatment strategy (represented in the lower left
quadrant of the cost-effectiveness plane), a numerically high
cost-effectiveness ratio would be favorable, whereas in the assessment of a more expensive but more efficient strategy (upper right quadrant), the opposite is true.17-19 The remaining quadrants represent situations where the evaluated strategy is more
expensive and less effective (dominated; upper left quadrant)
or less expensive and more effective (dominant; lower right quadrant). This taken into account by an additional graphic representation of the bootstrapping results in the cost-effectiveness
plane, with 95% and 50% confidence ellipses describing their
degree of uncertainty. To assess the robustness of the results,
sensitivity analyses were performed for changes in the duration of the initial hospitalization, expense for BNP testing, time
in the intensive care unit, cost of long-term medication, and
rehospitalization days with BNP guidance. The statistical analyses were performed with the SPSS/PC (version 13.0; SPSS Inc,
Chicago, Ill) and SAS/PC (version 8.2; SAS Institute Inc, Cary,
NC) software packages. A statistical significance level of .05
was used. All data were analyzed on an intention-to-treat basis. Comparisons were made by means of the t test, MannWhitney test, Fisher exact test, and 2 test as appropriate. Costs
were compared by bootstrap t tests. All hypothesis testing was
2 tailed. These analyses were prespecified in the BASEL study
protocol. The economic analysis was conducted in Swiss francs
and then converted to US dollars by using the average actual
currency conversion rate during the trial period.
RESULTS
Baseline demographic and clinical characteristics were
well matched between the 2 groups (Table 1). Mean
age was 71 years. In the BNP group, BNP levels were
less than 100 pg/mL in 80 patients (36%), 100 to 500
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Table 2. Outcomes in the BNP and Control Groups
Table 1. Baseline Characteristics in the BNP
and Control Groups*
Characteristic
Age, mean (SD), y
Women, No. (%)
History, No. (%)
Coronary artery disease
Arterial hypertension
Diabetes mellitus
COPD
Asthma
Pneumonia
Pulmonary embolism
Other pulmonary or pleural disease
Any pulmonary disease
Depressive disorder
Stroke or peripheral vascular disease
Chronic kidney disease
Deep vein thrombosis
Symptoms, No. (%)
Dyspnea†
Slight hill
Level ground
At rest
Paroxysmal nocturnal dyspnea
Nocturia
Chest pain
Coughing
Expectoration
Fever
Vital status, mean (SD)
Systolic blood pressure, mm Hg
Diastolic blood pressure, mm Hg
Heart rate, beats/min
Temperature, °C
Signs, No. (%)
Tachypnea (⬎20/min)
Elevated jugular venous pressure
Hepatojugular reflux
Rales
Wheezing
Hyperresonant percussion
Dullness
Cyanosis
Lower-extremity edema
Laboratory tests, mean (SD)
Hemoglobin, g/dL
Serum creatinine, mg/dL
Serum albumin, g/L
Final discharge diagnosis, No. (%)‡
Acute heart failure
Exacerbated COPD/asthma
Pulmonary embolism
Pneumonia
Anxiety disorder
Other disease§
Unknown cause
BNP Group
(n = 225)
Control Group
(n = 227)
70 (16)
93 (41)
71 (15)
97 (43)
113 (50)
113 (50)
47 (21)
75 (33)
17 (8)
30 (13)
18 (8)
20 (9)
119 (53)
15 (7)
40 (18)
56 (25)
19 (8)
112 (49)
124 (55)
56 (25)
65 (29)
12 (5)
28 (12)
13 (6)
26 (11)
107 (47)
21 (9)
49 (22)
56 (25)
22 (10)
32 (14)
125 (56)
66 (29)
79 (35)
60 (27)
76 (34)
101 (45)
72 (32)
59 (26)
33 (15)
132 (58)
58 (26)
87 (38)
76 (33)
78 (34)
123 (54)
87 (38)
50 (22)
146 (29)
85 (17)
96 (23)
37.6 (1.0)
145 (28)
86 (19)
99 (26)
37.4 (1.0)
106 (47)
32 (14)
25 (11)
103 (46)
55 (24)
22 (10)
20 (9)
14 (6)
73 (32)
104 (46)
32 (14)
24 (11)
104 (46)
45 (20)
17 (7)
26 (11)
19 (8)
83 (37)
13.5 (2.2)
1.28 (0.67)
34 (6)
13.4 (3.1)
1.31 (0.61)
33 (5)
101 (45)
51 (23)
10 (4)
32 (14)
7 (3)
26 (12)
8 (4)
116 (51)
25 (11)
11 (5)
30 (13)
9 (4)
33 (15)
12 (5)
Abbreviations: BNP, B-type natriuretic peptide; COPD, chronic obstructive
pulmonary disease.
SI conversion factor: To convert creatinine to micromoles per liter, multiply
by 88.4.
*There were no significant differences between the BNP group and the
control group.
†Four patients in the BNP group and 2 patients in the control group had
dyspnea only while walking up a steep incline.
‡P = .05 for the overall comparison of discharge diagnoses.
§Including interstitial lung disease, pneumothorax, pleural effusion, sepsis,
and anemia.
Variable
Control
Group
(n = 227)
Initial hospital visit
Total days in hospital,
8 (1-16)
10 (5-18)
median (IQR)
If admitted, median (IQR)
11 (6-19)
13 (8-21)
Total treatment cost,
5410 (6804) 7264 (7363)
mean (SD), $
All-cause mortality, No. (%)
13 (6)
21 (9)
At 90 d
Total days in hospital,
9 (1-19)
13 (6-24)
median (IQR)
Days in hospital
8.5 (1-19)
12 (6-23)
for dyspnea
Medication cost,
173 (137)
173 (127)
mean (SD), $
Total treatment cost,
6499 (7518) 9037 (8314)
mean (SD), $
All-cause mortality, No. (%)
32 (14)
36 (16)
At 180 d
Total days in hospital,
10 (2-24)
14 (6-27)
median (IQR)
Days in hospital
9 (1-20)
13 (6-24)
for dyspnea
Medication cost,
328 (253)
326 (267)
mean (SD), $
Total treatment cost,
7930 (8805) 10 503 (10 176)
mean (SD), $
All-cause mortality, No. (%)
44 (20)
52 (23)
P
Value
.002
.06
.006
.21*
.001
.001
.98
.001
.69*
.005
.003
.92
.004
.42*
Abbreviations: BNP, B-type natriuretic peptide; IQR, interquartile range.
*Fisher exact test.
pg/mL in 64 patients (28%), and greater than 500
pg/mL in 80 patients (36%). Testing of BNP induced
several important changes in patient treatment. Heart
failure was the final discharge diagnosis in 45% of
patients in the BNP group and 51% of patients in the
clinical group (P = .19). Exacerbation of obstructive
pulmonary disease was considered the cause of acute
dyspnea more often in the BNP group than in the
clinical group (23% vs 11%; P = .001) ( Table 2 ).
Follow-up was complete in 451 (99.8%) of 452
patients (Figure 1). Cost data were available equally
in both groups. Detailed data on outcomes and use of
specific resource in the hospital and during follow-up
are summarized in Tables 2, 3, and 4.
During the initial presentation to the ED, the use of
BNP levels significantly reduced the need for hospitalization and intensive care: 75% of patients in the BNP
group were hospitalized, as compared with 85% of those
in the control group (P = .008), and 15% of patients in
the BNP group required admission to the intensive care
unit, as compared with 24% of those in the control group
(P= .01) (Table 3). Moreover, the use of BNP levels reduced the need for ventilatory support and the number
of echocardiographic procedures performed during the
initial presentation. Patients assigned to the BNP group
spent significantly fewer days in the hospital than did patients in the control group (median, 8 days [interquartile range, 1-16 days] vs 10 days [interquartile range, 5-18
days]; P=.002) (Table 2). Total initial treatment cost was
significantly reduced in the BNP group ($5410 vs $7264
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BNP
Group
(n = 225)
Table 4. Specific Drugs Used in the Intensive Care Unit*
and at Hospital Discharge
665 Patients Screened
213 Ineligible or No Consent
Variable
452 Randomized
225 in BNP Group
227 in Control Group
225 Available for In-Hospital Analysis
227 Available for In-Hospital Analysis
In intensive care unit
Nitroglycerin IV
Nitroglycerin oral or transdermal
ACE inhibitors†
Loop diuretics IV
Thrombolysis
Antibiotics
Vasopressors or inotropic agents
Insulin IV
At hospital discharge
Diuretics
-Blockers
Nitroglycerin
ACE inhibitors†
Digoxin
Amiodarone
Aspirin
Anticoagulation
Inhaled bronchodilators
Inhaled corticosteroids
Oral corticosteroids
1 Lost to
Follow-up
224 Available for 90-d Analysis
227 Available for 90-d Analysis
224 Available for 180-d Analysis
227 Available for 180-d Analysis
Figure 1. Patient flow through trial.
Table 3. Use of Specific Resources in the BNP
and Control Groups*
During initial hospital visit
Intensive care
Time in ICU, mean (SD)
[median], h
Mechanical ventilation
(intubation)
Noninvasive ventilation
Any ventilatory support†
Pulmonary artery catheter
Coronary angiography
Echocardiography
Holter ECG
Exercise ECG
Myocardial perfusion SPECT
During 180-d follow-up
Coronary angiography
Echocardiography
Holter ECG
Exercise ECG
Myocardial perfusion SPECT
Control
Group
(n = 227)
33 (15)
10 (40) [0]
54 (24)
18 (47) [0]
P
Value
.01
.01
2 (1)
8 (4)
.11
13 (6)
14 (6)
0
12 (5)
91 (40)
8 (4)
8 (4)
6 (3)
20 (9)
28 (12)
5 (2)
20 (9)
112 (49)
11 (5)
10 (4)
9 (4)
.22
.03
.06
.15
.06
.49
.64
.44
7 (3)
33 (15)
8 (4)
14 (6)
14 (6)
7 (3)
38 (17)
6 (3)
11 (5)
12 (5)
⬎.99
.55
.58
.52
.67
Abbreviations: BNP, B-type natriuretic peptide; ECG, electrocardiogram; ICU,
intensive care unit; SPECT, single photon emission computed tomography.
*Values are expressed as number (percentage) of patients unless otherwise
indicated.
†Mechanical ventilation (intubation) or noninvasive ventilation.
in the control group; P=.006). The reduction in total treatment cost was mainly driven by the significant reduction in days in the hospital.
At 180 days, all-cause mortality was 20% in the BNP
group and 23% in the control group (P= .42) (Table 2).
Patients assigned to the BNP group spent significantly
fewer days in the hospital than those in the control group
(median, 10 days [interquartile range, 2-24 days] vs 14
days [interquartile range, 6-27 days]; P=.005). Total treatment cost was significantly reduced in the BNP group
($7930 vs $10 503 in the control group; P=.004). Again,
the reduction in total treatment cost was mainly driven
n = 33
15 (45)
8 (24)
16 (48)
25 (76)
1 (3)
14 (42)
2 (6)
4 (12)
n = 212
128 (60)
71 (33)
44 (21)
113 (53)
12 (6)
26 (12)
72 (34)
84 (40)
62 (29)
40 (19)
45 (21)
n = 54
11 (20)
8 (15)
22 (41)
31 (57)
2 (4)
26 (48)
9 (17)
6 (11)
n = 206
128 (62)
96 (47)
43 (21)
120 (58)
16 (8)
21 (10)
74 (36)
93 (45)
45 (22)
30 (15)
36 (17)
P
Value
.01
.27
.48
.08
⬎.99
.60
.20
⬎.99
.71
.006
⬎.99
.31
.39
.50
.67
.25
.08
.24
.33
1000
0.04%
0.02%
0
–1000
–2000
–3000
–4000
–5000
80.6%
–6000
–20
–15
19.3%
–10
–5
0
5
10
15
Difference in Mortality Rates, %
Figure 2. Results for incremental 180-day cost-effectiveness of B-type
natriuretic peptide (BNP) guidance from 5000 bootstrap replications. The
outer ellipse defines the 95% confidence region for true incremental
cost-effectiveness of BNP guidance compared with only clinical guidance.
The inner ellipse defines the 50% confidence region. The center of the ellipse
represents our point estimate of incremental costs and effects. Each
percentage indicates the estimated probability that the incremental
cost-effectiveness of BNP guidance obtained from a bootstrap sample lies in
that quadrant. In 80.6% of bootstrapping replications, BNP guidance was
less expensive and resulted in lower mortality; in 19.3% it was less
expensive and resulted in higher mortality. In less than 0.1% of replications
was BNP guidance more expensive and associated with either higher or
lower mortality. Comparison of mortality, P = .42; comparison of costs
(bootstrap t test), P = .004.
by the reduction in days in the hospital. Results for incremental 180-day cost-effectiveness of BNP guidance are
displayed in Figure 2.
As shown in Table 5, the cost-effectiveness of BNP
guidance was robust to changes in several variables, but
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Control
Group
Abbreviations: ACE, angiotensin-converting enzyme; BNP, B-type natriuretic
peptide; IV, intravenous.
*Within the first 24 hours.
†Or angiotensin receptor blockers.
Difference in Costs/Patient, $
Variable
BNP
Group
(n = 225)
BNP
Group
Table 5. Sensitivity Analyses: Effect of Changes in Variables on Differences in Initial and 180-Day Total Treatment Cost*
Initial Total Treatment Cost
Variable
Duration of initial hospitalization† (both groups), %
−10
−20
−30
Cost per day in hospital, $‡
−150
As in this trial
⫹150
⫹300
Cost for outpatient visit, $§
−100
As in this trial
⫹100
⫹200
Cost for intensive care, $/h
−25
As in this trial
⫹25
⫹50
Expense for BNP testing, $
100
47 (as in this trial)
25
10
Time in ICU with BNP guidance, h 㛳
⫹1
⫹3
⫹5
Cost of long-term medication with BNP guidance, %
−25
As in this trial
⫹25
⫹50
⫹100
Rehospitalization days with BNP guidance¶
−1
As in this trial
⫹1
⫹2
⫹3
180-d Total Treatment Cost
Change, $/Patient
P Value
Change, $/Patient
P Value
−1665
−1475
−1285
.006
.006
.006
−2385
−2198
−2010
.005
.006
.007
−1377
−1854
−2332
−2808
.008
.006
.005
.005
−1785
−2573
−3362
−4150
.006
.004
.004
.004
−1864
−1854
−1844
−1834
.006
.006
.006
.006
−2583
−2573
−2564
−2554
.004
.004
.004
.004
−1668
−1854
−2042
−2229
.005
.006
.007
.008
−2387
−2573
−2759
−2945
.005
.004
.004
.004
−1801
−1854
−1876
−1891
.007
.006
.005
.005
−2520
−2573
−2595
−2610
.005
.004
.004
.004
−1769
−1597
−1426
.008
.02
.03
−2487
−2316
−2144
.006
.01
.02
−1854
−1854
−1854
−1854
−1854
.006
.006
.006
.006
.006
−2654
−2573
−2491
−2409
−2245
.003
.004
.006
.008
.01
−1854
−1854
−1854
−1854
−1854
.006
.006
.006
.006
.006
−3421
−2573
−1725
−877
−30
⬍.001
.004
.06
.33
.97
Abbreviations: BNP, B-type natriuretic peptide; ICU, intensive care unit.
*Positive values indicate that BNP guidance is more expensive; negative values indicate that BNP guidance is less expensive.
†In patients hospitalized, assuming an equal reduction in high-cost units and low-cost units, as well as no change in those treated as outpatients.
‡Assuming no change in outpatient cost.
§Assuming no change in inpatient cost.
㛳On average for all patients in the BNP group, assuming no change in the overall time to discharge.
¶On average for all patients in the BNP group initially discharged alive, assuming an average total cost of $900 per day.
sensitive to changes in rehospitalization days with BNP
guidance.
Subgroup analysis showed that the benefit of BNP testing to reduce total treatment cost at 180 days was particularly evident in patients with a history of coronary
artery disease ($8566 vs $12 194 in the control group;
P=.005) and in patients with a history of pulmonary disease ($8876 vs $12 408 in the control group; P= .01).
COMMENT
We performed cost-effectiveness analyses of BNP testing
in patients presenting to the ED with acute dyspnea. To
address the fact that tailoring of resources may very well
be cost-effective initially but result in large secondary
costs due to recurrent symptoms and potentially even
increased mortality, cost-effectiveness analyses were performed at 180 days of follow-up. As our major finding,
we report that BNP testing is cost-effective. The use of
BNP levels significantly reduced total treatment cost.
This reduction was driven by significantly fewer days
spent in the hospital in the BNP group. A large part of
this reduction in days in the hospital and cost occurred
during the initial presentation and was fully maintained
at 180 days. Sensitivity analyses demonstrated that this
observation was robust to changes in most variables but
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sensitive to changes in rehospitalization with BNP guidance. Subgroup analysis showed that the benefit of BNP
testing was particularly evident in patients with a history
of either coronary artery disease or pulmonary disease.
We extrapolate that the impact of BNP testing observed
in our study also applies to patients presenting to North
American hospitals. Beyond doubt, North American
hospitals differ in several aspects from European hospitals. However, as disease prevalence, 1 - 3 patient
characteristics,1-3,5,6,20 treatment strategies,1-3,5,6,20 and
total cost of treatment1-3 are remarkably similar, this
extrapolation seems justified. In 1997, an estimated
$5501 was spent for every hospital discharge diagnosis
of HF in North America.1-3 Estimated total 1-year treatment cost was $5037 in patients with stage II chronic
obstructive pulmonary disease and $10 812 in patients
with stage III chronic obstructive pulmonary disease.21
Moreover, our results should apply in all major health
care systems. In a health care system in which reimbursements are governed by a system of diagnosis
related groups (DRGs), similar cost savings should arise
as the DRGs are generally higher for HF than for chronic
obstructive pulmonary disease. In nations with nationalized health care, the reductions in total days in the hospital will release resources for other patients and may
therefore result in a reduction in waiting periods for
elective in-hospital procedures.
These long-term follow-up data are reassuring given
recent criticism regarding the value of BNP testing in clinical medicine, and they considerably extend the evidence regarding the cost-effectiveness of this marker.22-24
The use of BNP levels in patients presenting to the ED
with acute dyspnea has several beneficial effects on patient treatment that, in summary, lead to reduction in resource utilization and significantly improved costeffectiveness. First, the use of BNP levels significantly
increases diagnostic accuracy.5,6,9,10,25 This reduces the
number of patients incorrectly diagnosed and therefore
incorrectly treated. Second, the use of BNP levels allows
more rapid diagnosis and therefore more rapid initiation of the appropriate therapy.11 Third, more rapid initiation of the appropriate therapy results in more favorable short-term patient outcome as quantified by a
reduction in the need for hospital admission or intensive care. This finding is supported by recent data from
ADHERE (Acute Decompensated Failure National Registry) showing that early use of intravenous nitroglycerin or nesiritide may improve in-hospital outcomes.26
Early diagnosis of HF by means of BNP seems to expedite effective drug treatment, as in the intensive care unit
intravenous nitroglycerin was used more often in the BNP
group. Given the enormous public health burden of HF,1-4
this is of paramount importance.
Little is known regarding the cost-effectiveness of most
diagnostic tests currently used in clinical practice. This
lack of data also applies to the measurement of troponin
in patients with acute chest pain, the measurement of Ddimers in patients with suspected pulmonary embolism,27 and tests performed in the screening for cancer
including prostate-specific antigen in elderly men,28 among
others. Obviously, it would be far more difficult for a single
diagnostic test performed at a unique point in patient pre-
sentation to impact on mortality or total cost of disease
than it would, for example, for prolonged medical therapy
or prolonged benefit from implantation of a defibrillator or pacemaker.29 The use of BNP levels also seems to
provide the potential for cost savings in other indications. These include the screening of asymptomatic left
ventricular dysfunction30 and the optimization of medical therapy in patients with chronic HF.31
In the BASEL study, BNP testing reduced the rate of
hospital admission, the rate of admission to intensive care,
and the time to discharge. No indication was found that
the early benefits in the BNP group were counterbalanced by worse outcome or higher resource utilization
during follow-up. This is of particular interest, as the use
of BNP affected not only the initial resource utilization,
including intensive care and echocardiography, but also
the quantitative distribution of diagnoses, with a higher
detection rate of exacerbated obstructive pulmonary disease in the BNP group. Accordingly, -blockers were prescribed less often at hospital discharge in the BNP group.
The BASEL study included unselected consecutive patients presenting with acute dyspnea. Recent data5,6 suggested that BNP levels are most useful in patients with
an intermediate clinical probability of HF. Whether restricting BNP measurements to patients in this subgroup would yield medical and economic long-term benefits similar to those observed in this study is unknown.
Moreover, the approach used in the BASEL study has obvious logistical advantages. Delaying the venipuncture
for BNP until the physician has collected all clinical data
to determine whether an individual patient in fact has
an intermediate clinical probability of HF would significantly increase the time to the correct diagnosis and, accordingly, the time to appropriate treatment in patients
who might benefit the most from BNP testing. Because
BNP testing is noninvasive, simple, and inexpensive, measuring BNP directly at presentation in all patients with
acute dyspnea seems to be a reasonable strategy. Moreover, in addition to the diagnostic utility, BNP levels do
provide valuable prognostic information in patients with
HF. The action resulting from this prognostic information may have contributed to the improved outcomes of
the patients in the BNP group.32
A particular strength of our study is that the study
population was highly representative of the elderly population of patients with acute dyspnea in clinical practice.1-3 The mean age was 71 years, nearly half the patients were women, and coexisting conditions were
common. The rapid and accurate differentiation of HF
from other causes of acute dyspnea and corresponding
long-term management of HF in such patients is often
difficult.
Several limitations apply to this study. First,
resource use was limited to key items collected in the
BASEL study. Second, the results are generalizable
only to patients presenting to the ED. It is unknown to
what extent the effects of BNP testing observed in this
setting can be extrapolated to patients presenting to
physicians in private practice. Initial experience is
promising but requires confirmation by additional
studies.25 Third, the interpretation of BNP levels was
based on the data available when the study protocol
(REPRINTED) ARCH INTERN MED/ VOL 166, MAY 22, 2006
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was devised. More recent data have suggested that 200
to 225 pg/mL rather than 100 pg/mL is the most
appropriate lower cutoff value in patients with renal
disease.20,33 In contrast, the presence of obesity seems
to require the use of lower cutoff values.34,35
In conclusion, this study in patients presenting to the
ED with acute dyspnea demonstrates that rapid BNP testing is cost-effective during the initial hospital encounter as well as at 180 days.
Accepted for Publication: December 27, 2005.
Correspondence: Christian Mueller, MD, Department of
Internal Medicine, University Hospital, Petersgraben 4,
CH-4031 Basel, Switzerland (chmueller@uhbs.ch).
Financial Disclosure: None.
Funding/Support: This study was supported by research grants from the Swiss National Science Foundation, Swiss Heart Foundation, Novartis Foundation, Krokus
Foundation, and University of Basel (Dr Mueller). Diagnostic devices and reagents (Triage) were provided by
Biosite.
Role of the Sponsor: The funding sources had no role
in study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit the manuscript for publication.
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