Clinical Chemistry 53: 1415-1422, 2007.
First published June 22, 2007; 10.1373/clinchem.2006.081448
(Clinical Chemistry. 2007;53:1415-1422.)
© 2007 American Association for Clinical Chemistry, Inc.
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Evidence-Based Laboratory Medicine and Test Utilization |
Medical and Economic Long-term Effects of B-Type Natriuretic Peptide Testing in Patients with Acute Dyspnea
Tobias Breidthardt1,
Kirsten Laule1,
Anne-Henny Strohmeyer1,
Christian Schindler2,
Sophie Meier1,
Michael Fischer1,
André Scholer3,
Markus Noveanu1,
Michael Christ1,
André P. Perruchoud1 and
Christian Mueller1,a
1 Department of Internal Medicine, University Hospital, Basel, Switzerland.
2 Institute for Social and Preventive Medicine, Basel, Switzerland.
3 Department of Laboratory Medicine, University Hospital, Basel, Switzerland.
aAddress correspondence to this author at: Department of Internal Medicine, University Hospital, Petersgraben 4, CH 4031 Basel, Switzerland. Fax 0041-61-2655353; e-mail chmueller{at}uhbs.ch.
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Abstract
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Background: The objective of this prospective study was to assess the medical and economic long-term effects of using B-type natriuretic peptide (BNP) concentrations in the management of patients with acute dyspnea.
Methods: We performed follow-up analysis of the B-Type Natriuretic Peptide for Acute Shortness of Breath Evaluation, a randomized study including 452 patients who presented to the emergency department with acute dyspnea. Participants were randomly assigned to a diagnostic strategy involving the rapid measurement of BNP concentrations (n = 225) or standard assessment (n = 227). Mortality was assessed at 720 days, morbidity and economic data at 360 days.
Results: BNP testing induced several important changes in initial patient management, including a reduction in the initial hospital admission rate, the use of intensive care, and initial time to discharge. At 720 days, 172 deaths had occurred. Cumulative all-cause 720-day mortality was not different between the BNP group (37%) and the control group (36%, P = 0.6). Morbidity as reflected by days spent in-hospital at 360 days was significantly lower in the BNP group [median 12 days ([interquartile range 2–28 days)] compared with the control group [median 16 (7–32)] days, P = 0.025]. Functional status was similar in both groups. Economic outcome as quantified by total treatment cost at 360 days was significantly improved in the BNP group (mean $10 144 vs $12 748 in the control group, P = 0.008).
Conclusions: Rapid BNP testing in patients with acute dyspnea has no effect on long-term mortality. However, morbidity as quantified by days spent in-hospital and economic outcome are still improved at 360 days.
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Introduction
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The evaluation and management of patients presenting to the emergency department (ED)1
with acute dyspnea is challenging. Among more than 30 diagnoses that may be responsible for acute dyspnea, heart failure (HF) is very common and clinically important (1)(2)(3). Unfortunately, the rapid and accurate differentiation of HF from other causes of acute dyspnea often remains elusive. Misdiagnosis of HF can lead to morbidity, mortality, and increased resource utilization. The cost of HF is estimated to be $100 billion a year in Europe and the US, 70% of which is due to hospitalization (1)(2)(3). Therefore, accurate and cost-effective diagnosis and management of HF is of paramount importance.
B-type natriuretic peptide (BNP) seems to be extremely helpful in this setting. BNP concentrations are quantitative markers of HF—the more severe the disease, the higher the BNP concentration (4)(5). The use of BNP concentrations in addition to clinical judgment significantly increases the accuracy of the clinical evaluation (6)(7)(8)(9). The randomized B-Type Natriuretic Peptide for Acute Shortness of Breath Evaluation (BASEL) study showed that the use of BNP concentrations improved initial patient management and was cost-effective at 6 months (10)(11). It is currently unknown whether the use of BNP concentrations may also affect mortality. Although subgroup analysis suggested that the use of BNP may reduce initial mortality in frail elderly patients, long-term follow-up with a sufficient number of events was considered mandatory before definite conclusions were possible regarding the effect of BNP on mortality (12).
The introduction of a diagnostic test that considerably influences management and therapeutic decisions mandates meticulous surveillance regarding medical and economic long-term consequences. Given recent criticism regarding its diagnostic value and the fact that it affects the final discharge diagnoses, this is particularly true for BNP testing (10)(11)(12)(13)(14)(15). We therefore planned and prospectively performed a 12-month follow-up evaluation of all patients enrolled in the BASEL study regarding all-cause mortality, hospitalizations, functional status, and total treatment cost. The specific aims of this follow-up study were to assess whether the changes in the initial management induced by BNP testing would affect long-term mortality, whether the observed initial reduction of days in-hospital would still be present at 12 months, and whether the initial savings would be maintained or counterbalanced.
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Patients and Methods
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patient population
The design, methods, and primary results of BASEL have been reported (10). In brief, 452 patients presenting with acute dyspnea to the ED of the University Hospital in Basel, Switzerland, were enrolled in this prospective, randomized, controlled single-blind trial. Patients were excluded for a traumatic cause of dyspnea, severe renal disease (defined by a serum creatinine concentration of >250 µmol/L), cardiogenic shock, and request for an early transfer to another hospital. There were no limitations to study entry according to the time of day at which patients arrived in the ED or the availability of research staff. Group assignment was accomplished with the use of a computer-generated randomization scheme in a 1:1 ratio without stratification. We randomly assigned 225 patients to a diagnostic strategy with the use of BNP concentrations and 227 to the conventional diagnostic strategy.
procedures
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. BNP was measured with the Biosite Triage® immunoassay (Biosite Diagnostics). In the BNP-guided group, diagnostic and therapeutic decisions were not based on BNP concentrations only; instead, this information was considered in the context of the other clinical information obtained and the physicians’ clinical impressions, as described (10)(16). We used 2 BNP cutoff concentrations (rule out, 100 ng/L, and rule in, 500 ng/L) to separate HF from other causes of dyspnea. In patients with a BNP concentration <100 ng/L, HF was considered unlikely, and alternative causes of dyspnea had to be pursued. In patients with a BNP concentration >500 ng/L, HF was considered likely and rapid therapy with diuretics, nitroglycerin, ACE inhibitors, and morphine was recommended. The majority of patients with BNP concentrations between 100 and 500 ng/L were considered to have mild to moderate HF, but the protocol recommended clinical judgment and possible further diagnostic testing to exclude, e.g., pulmonary embolism, pneumonia, and pulmonary hypertension. Patients in the control group were evaluated and treated according to the most recent clinical guidelines (3)(17). At the time of the BASEL study, BNP testing was not available for outpatients in Switzerland.
survival and resource use
We obtained data on survival from the time of randomization to the end of study follow-up and the use of specific healthcare resources. Patients were contacted by telephone interview at 180, 360, and 720 days after the initial presentation. In addition, referring physicians were contacted. We assessed mortality at 720 days and morbidity and economic data at 360 days. Detailed medical and economic follow-up at 360 days was complete in 451 of 452 patients (99.8%). All-cause mortality could be assessed at 720 days, because the median time from randomization to last patient contact or patient death was 701 days. The high number of deaths that occurred within 720 days gave this analysis sufficient statistical power to examine mortality. The calculation of total days in-hospital and total cost of treatment included all hospitalizations after the initial presentation to ED (thus also including the index hospitalization of those patients admitted at the initial presentation to the ED). Because ratios of costs to charges have not been defined for the majority of services and departments at our institution, we used hospital charges as the most appropriate estimate of the true costs (18)(19). To avoid an imbalance due to differences in reimbursement or charges associated with different types or classes of insurance, we standardized charges according to the actual rates for patients with general insurance who were living in Basel. 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 <24 h but with stay overnight in the ED, $381; for every hour in the intensive care unit, $85.60. 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 rather than BNP testing. For the cost of BNP testing, we used the reimbursement for the measurement of BNP in Switzerland in 2002 ($47). Due to the short follow-up period, cost during follow-up was not deflated. All endpoints 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.
cost-effectiveness analysis
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 the control group. We calculated mean cost 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 (20)(21)(22)(23). We used nonparametric bootstrap to estimate 95% CI for differences in average costs and for the incremental cost-effectiveness 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 (20)(21)(22)(23). Uncertainties surrounding costs, benefits, and cost-effectiveness were represented by confidence ellipses in the "cost-effectiveness plane" (20)(21)(22)(23). The presentation of cost-effectiveness results as cost-effectiveness ratios with 95% CI is inappropriate, because CIs of costs (i.e., the numerator of the cost-effectiveness ratio) and effects (i.e., the denominator of the cost-effectiveness) are multiplied, and also insufficient, because the interpretation of cost-effectiveness ratios depends on the quadrants of the cost-effectiveness plane into which incremental costs and effects fall. 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. 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 was taken into account by an additional graphical representation of the bootstrapping results in the cost-effectiveness plane, with 95% and 50% confidence ellipses describing their degree of uncertainty.
statistical analysis
We performed statistical analyses by use of the SPSS/PC (version 13.0, SPSS) and the SAS/PC (version 8.2, SAS) software packages. A statistical significance level of 0.05 was used. We analyzed all data on an intention-to-treat basis. We made comparisons using the t-test, Mann–Whitney U-test, Fisher exact test, and 
2 test as appropriate. We compared costs using 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$ using the average actual currency conversion rate during the trial period. The cumulative survival curves were constructed by the Kaplan–Meier method.
role of the funding source
The funding source of the study 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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Results
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Baseline demographic and clinical characteristics were well matched between the 2 groups (Tables 1
and 2
). At 720 days, 172 deaths had occurred. Cumulative all-cause 720-day mortality was not different between the BNP group (37%) and the control group (36%, P = 0.6; Fig. 1
). Mortality was also comparable in the prespecified subgroup of elderly patients defined as age 
70 years (44% vs 46%, P = 0.9).
Morbidity as reflected by days spent in-hospital at 360 days was significantly lower in the BNP group [median 12 days (interquartile range 2–28 days)] compared with the control group [median 16 (7–32) days, P = 0.025]. The vast majority of the days spent in-hospital were for hospitalizations due to dyspnea (including the index hospitalization). Moreover, the reduction in in-hospital days in the BNP group was exclusively due to the reduction in days spent in-hospital due to dyspnea. Functional status at 360 days was similar in both groups, with 65% and 70% of patients in New York Heart Association (NYHA) class I or II (P = 0.6). Economic outcome at 360 days as quantified by total treatment cost was significantly improved in the BNP group (mean $10 144 vs $12 748 in the control group, P = 0.008; Fig. 2A
). The reduction in total treatment cost occurred during the initial presentation and was maintained at 360 days (Fig. 2B
).
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Figure 2. Cumulative frequency distribution curves for the total 360-day treatment cost (P = 0.008; A) and mean total treatment cost over time (B) of patients BNP group compared with the control group.
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Results for incremental cost-effectiveness of BNP guidance are displayed in Fig. 3
. In 39.5% of bootstrapping replications at 360 days, BNP guidance was less expensive and resulted in lower mortality; in 59.1% it was less expensive and resulted in higher mortality (P = 0.83 for mortality rates). In <1% of replications was BNP guidance more expensive and associated with either higher or lower mortality.
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Figure 3. Results for incremental cost-effectiveness of BNP guidance from 5000 bootstrap replications at 360 days.
The outer ellipse defines the 95% confidence region for true incremental cost-effectiveness of BNP guidance compared with clinical guidance only. The inner ellipse defines the 50% confidence region. The center of the ellipse represents our point estimate of incremental costs and effects. The percentages indicate the estimated probability that the incremental cost-effectiveness of BNP guidance obtained from a bootstrap sample lies in the respective quadrants.
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Discussion
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This study examined the medical and economic long-term effects of rapid BNP testing in patients presenting to the ED with acute dyspnea. We report 3 major findings. First, use of BNP had no effect on long-term mortality. This analysis had a 70% power to detect a 10% difference (decrease or increase with BNP guidance) in mortality with an 
error of 0.05. Of note, the reduction in initial mortality observed in frail elderly patients was no longer evident at 720 days (12). The mortality rate observed in this randomized controlled trial was similar to that reported in prospective observational studies including unselected patients with acute dyspnea (24). This observation supports the notion that the BASEL study included consecutive "real-life" patients and that its findings are therefore applicable to most ED settings. In addition, the high mortality rate observed highlights the need for further improvement in the clinical management of patients with acute dyspnea. The neutral effect of BNP testing on mortality in our study does not preclude that BNP testing may have an impact on long-term mortality in other clinical settings, e.g., the use of serial BNP measurements to tailor and monitor therapy once the diagnosis of HF has been established (25)(26)(27).
Second, the use of BNP concentrations in conjunction with other clinical information significantly reduced morbidity, as reflected by a reduction in days in-hospital without compromising functional status at 360 days. Overall, functional status at 360 days was satisfying, with two-thirds of patients having either no or only slight limitations of their daily activities due to dyspnea. These long-term follow-up data are reassuring given recent criticism regarding the value of BNP testing in clinical medicine and considerably extend the evidence regarding the safety and effectiveness of the use of this marker (13)(14)(15).
Third, the reduction in days spent in-hospital was the major driver for a significant reduction in total treatment cost at 360 days. Therefore, BNP seems to be a safe and effective help in tailoring one of our most expensive healthcare resources. This observation is supported by recent findings from the REDHOT (Rapid Emergency Department Heart Failure Outpatient Trial) study (28). In this prospective observational study, an ED doctor’s intention to admit or discharge a patient had no influence on 90-day outcomes, whereas BNP concentration was a strong predictor of 90-day outcome. The 90-day combined event rates (HF visits or admissions and mortality) in the group of patients admitted with BNP <200 ng/L and >200 ng/L were 9% and 29%, respectively (P = 0.006). Given the enormous public health burden of HF, attempts to use healthcare resources more appropriately are of paramount importance (1)(2)(3)(16). In the BASEL study, BNP testing reduced the rate of hospital admission, the rate of admission to intensive care, and the time to discharge (10). If this tailoring of resources had been inappropriate for the patients in the BNP-guided group, recurrent symptoms invariably would have resulted in increased hospitalizations and resource utilization during long-term follow-up. Our analysis clearly shows that the early benefits were maintained at 12 months. BNP testing reduced the long-term treatment cost by 27%, or $2350 per patient. Because hospitalizations and therefore days in-hospital are a major contributor to total treatment cost, endpoints reflecting morbidity and endpoint-quantifying economic outcome clearly interact. Therefore, the 2 effects observed should not be viewed as independent of each other.
Although disease prevalence (1)(2)(3), patient characteristics (1)(2)(3)(8)(9)(10), treatment strategies (1)(2)(3)(8)(9)(10)(17), and total cost of treatment (1)(2)(3) are remarkably similar in North America and Europe, the extrapolation of our findings to North America seems justified. The total cost of treatment in this study was comparable with healthcare expenditures in the US. In 1997, an estimated $5501 was spent for every hospital-discharge diagnosis of HF (1)(2)(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 (29). Despite the similarities mentioned above, it is important to note that the length of hospital stay in the US is shorter than in Europe and therefore in this study. Although the absolute reduction in total days in-hospital would be less in the US, the relative reduction most likely is comparable. Because shorter hospitalizations are very often associated with a higher rate of recurrent hospitalizations, BNP testing could potentially also lead to even greater savings in the US by avoiding more recurrent hospitalizations. In a health system in which reimbursements are governed by a diagnosis-related group system, similar cost savings should arise, because the diagnosis-related groups are generally higher for HF than for chronic obstructive pulmonary disease. In nations with nationalized healthcare, the reductions in total days in-hospital will release resources for other patients and may therefore result in a reduction in waiting periods for elective in-hospital procedures.
The findings of the BASEL study extend the conclusions of observational studies in which BNP concentrations were validated by comparison with a retrospectively adjudicated gold-standard diagnosis of HF by 2 independent cardiologists (6)(7)(8)(9). In the Breathing Not Properly Multinational Study, BNP concentrations by themselves were more accurate than any historical or physical finding or laboratory value in identifying HF as the cause of acute dyspnea. Our data, together with detailed analyses from the Breathing Not Properly Multinational Study, strongly support the use of 2 cutoff values in patients with acute dyspnea: one with a high negative predictive value to reliably rule out HF, and one with a high positive predictive value to reliably rule in HF. As consistently shown in this study and the Breathing Not Properly study, 
70% to 75% of patients with acute dyspnea present with either low (<100 ng/L) or high (>500 ng/L) BNP concentrations (8)(9). It is not clear from current data whether the percentage of patients with intermediate BNP concentrations is significantly higher if BNP testing is restricted to those patients in whom the diagnosis of acute dyspnea is not clear after standard testing (8)(9). In addition to their diagnostic utility, BNP concentrations do provide valuable prognostic information in patients with HF. This prognostic information may have contributed to the improved morbidity and economic outcomes of the patients in the BNP group (28).
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)(2)(3). Mean age was 71 years, nearly half the patients were women, and coexisting conditions were very common. The rapid and accurate differentiation of HF from other causes of acute dyspnea and corresponding long-term management in such patients is often very difficult.
Several limitations apply to this study. First, the interpretation of BNP concentrations was based on the data available when the study protocol was devised. Whereas subgroup analyses from the Breathing Not Properly Multinational Study confirmed our approach not to adjust cutoff values for age and sex, 2 conditions have evolved as important cofounders in the interpretation of BNP concentrations: kidney disease and obesity (8)(9)(30)(31)(32). In patients with kidney disease and an estimated glomerular filtration rate <60 mL/min, 200–225 ng/L rather than 100 ng/L is the most appropriate cutoff value to rule out HF (30)(31). In contrast, the presence of obesity seems to require the use of lower cutoff values (32). Second, this study recruited patients presenting with acute dyspnea 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 (19). One such study, BASEL III Private Practice, has recently finished patient enrollment. Unresolved issues include the most appropriate cutoff values in private practice. Third, resource use was limited to key items collected in the BASEL study.
In conclusion, rapid BNP testing in patients with acute dyspnea has no effect on long-term mortality. However, morbidity, as quantified by days spent in-hospital, and economic outcome are improved at 12 months without any detrimental effects on functional status. These data provide additional support for the inclusion of BNP testing in the management of patients with acute dyspnea.
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Acknowledgments
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Grant/funding support: This study was supported by research grants from the Swiss National Science Foundation, the Swiss Heart Foundation, the Novartis Foundation, the Krokus Foundation, and the University of Basel (to C.M.). Diagnostic devices and reagents (Triage) were provided by Biosite (San Diego, CA).
Financial disclosures: C.M. has received research support from Biosite, Brahms, Abbott, and Roche; and speaker’s honoraria from Abbott, Bayer, Biosite, Brahms, Dade Behring, and Roche.
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Footnotes
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1 Nonstandard abbreviations: ED, emergency department; HF, heart failure; BNP, B-type natriuretic peptide; BASEL, B-Type Natriuretic Peptide for Acute Shortness of Breath Evaluation; NYHA, New York Heart Association. 
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Abstract
Introduction
