Admission B-Type Natriuretic Peptide Levels and In-Hospital Mortality in Acute Decompensated Heart Failure

Methods

Data used to determine risk associated with BNP levels were taken from ADHERE. This registry collects detailed hospitalization data from initial presentation in the hospital or emergency department until discharge, transfer, or in-hospital death (19,20). The ADHERE registry contains data on patients hospitalized with acute decompensated HF in community, tertiary, and academic centers from all regions of the country (20). For the purpose of the registry, acute decompensated HF is defined as new-onset decompensated HF or decompensation of chronic, established HF with symptoms sufficient to warrant hospitalization. The design, methods, and patient characteristics in ADHERE have been described previously (19). Briefly, medical records are reviewed at participating study sites, and data from consecutive eligible male and female patients ≥18 years of age at the time of hospitalization are entered in the registry using an electronic case report form incorporating real-time validity checking (19,20). These data include demographic information, medical history, baseline clinical characteristics, initial evaluation, treatment received, procedures performed, hospital course, and patient disposition. Standardized definitions are used for all patient-related variables, clinical diagnoses, and hospital outcomes. Importantly, registry participation does not require any alteration of treatment or hospital care, and entry of data into the registry is not contingent on the use of any particular therapeutic agent or treatment. Institutional review board approval is required for all participating centers; however, informed consent of individuals was not required for registry entry. To preserve patient confidentiality, direct patient identifiers are not collected, and data are reported only in aggregate format. Therefore, registry entries reflect individual hospitalization episodes, not individual patients, and multiple hospitalizations of the same patient may be entered into the registry as separate records.

In the beginning of 2003, ADHERE hospitals began employing the expanded range BNP testing (range 0 to 5,000 pg/ml). This current study analyzed ADHERE data from April 2003 through December 2004 (February 2005 data transfer). During this time frame 191 of 229 ADHERE hospitals reported having the capability of assessing BNP levels (176 BNP only, 15 BNP and NT-proBNP, 14 NT-proBNP only, and 24 none). B-type natriuretic peptide levels on presentation (first level obtained within 24 h of presentation) were analyzed by the local hospital laboratory and recorded in the medical record. During the analysis time frame, 48,629 (63%) of 77,467 patients episodes had BNP assessment. For the primary analyses, patients were grouped by BNP quartiles. Data were analyzed for the overall cohort as well as for those patients with reduced (left ventricular ejection fraction [LVEF] <40%) and preserved (LVEF ≥40%) systolic function. Analysis of patients with LVEF ≥50% was also performed. Data were also assessed for each weight category by body mass index (BMI) (kg/m²): underweight (BMI <18.5), healthy weight (BMI 18.5 to 24.9), overweight (BMI 25.0 to 29.9), and obese (BMI ≥30).

Results

From April 2003 through December 2004, there were 48,629 (63%) of 77,467 patient episodes in 191 hospitals that had BNP assessment within 24 h of presentation. The BNP testing rate increased over time from 51.2% in second-quarter 2003 to 75.4% in fourth-quarter 2004 (p < 0.0001). The distribution of BNP for these acute HF hospitalizations is shown in Figure 1.B-type natriuretic peptide levels were <100 pg/ml in 3.3% of the total cohort. Quartiles (Q) of BNP were Q1 (<430 pg/ml), Q2 (430 to 839 pg/ml), Q3 (840 to 1,729 pg/ml), and Q4 (≥1,730 pg/ml).

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Figure 1

Distribution of BNP Values

Histogram of B-type natriuretic peptide (BNP) values (pg/ml) among the 48,629 hospitalization episodes.

Patient characteristics as stratified by BNP quartiles are shown in Table 1.Patients in BNP Q1 versus Q4 were slightly younger (mean age 71.5 vs. 73.9 years) and were more likely to be women (55% vs. 49%). A greater proportion of African Americans (22% vs. 16%) were in Q4 versus Q1. Patients in Q1 versus Q4 were less likely to have a history of HF and coronary artery disease and were half as likely to have a history of chronic renal insufficiency, but these patients had a greater prevalence of a history of diabetes (Table 1). Notably, there were few clinically relevant differences observed in the admission signs and symptoms of HF by BNP quartile. Somewhat higher systolic blood pressure and lower creatinine levels were associated with a lower BNP quartile. Patients in BNP Q4 were more than twice as likely to have moderate to severe impairment in LVEF (Q1 29% vs. Q4 70%).

In-hospital medication use by BNP quartiles is shown in Table 2.Most patients received intravenous diuretics (90% to 94%), and there were only small differences by BNP quartile. More than twice as many patients in BNP Q4 versus Q1 were treated with inotropic agents or nesiritide, whereas there was little difference in nitroglycerine use by BNP quartiles (Table 2). Use of beta-blockers and digoxin during hospitalization was modestly more frequent in patients in higher BNP quartiles. Use of ultrafiltration and dialysis was significantly more frequent in higher BNP quartile patients (Table 2).

The in-hospital mortality risk for the overall patient population was 3.6% (1,760 of 48,629). There was a near-linear relationship between BNP and in-hospital mortality: Q1 (1.9%), Q2 (2.8%), Q3 (3.8%), and Q4 (6.0%), p < 0.0001 (Fig. 2).For the 1,407 patients with BNP levels at or above 5,000 pg/ml, the in-hospital mortality was 8.5%. B-type natriuretic peptide quartiles were highly predictive of mortality even after adjustment for age, gender, SBP, BUN, creatinine, sodium, pulse, and dyspnea at rest, Q4 versus Q1, adjusted odds ratio 2.23 (95% confidence interval 1.91 to 2.62), p < 0.0001, as shown in Table 3.The area under the receiver-operator curve for the model was 0.77, indicating adequate model discrimination (Table 3). Addition of up to 40 additional demographic, medical history, outpatient medications, and initial assessment variables produced similar findings (area under the curve 0.79). As a continuous variable, BNP was also predictive of mortality (Fig. 3).In multivariable analysis, for every 400-U increase in BNP, the odds of risk-adjusted mortality were 9% higher (odds ratio 1.09, 95% confidence interval 1.08 to 1.11, p < 0.0001).

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Figure 2

Relationship Between BNP Quartiles and In-Hospital Mortality

In-hospital mortality rates by B-type natriuretic peptide (BNP) quartiles (Q) (unadjusted) in the entire patient cohort (A), in patients with left ventricular ejection fraction (LVEF) <40% (n = 19,544) (B), in patients with LVEF ≥40% (n = 18,164) (C), and in patients with LVEF ≥50% (n = 12,631) (D). Each among-group comparison p < 0.0001.

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Figure 3

Scatterplot Smoother of BNP Levels and In-Hospital Mortality

Local regression scatterplot smoother (loess) of B-type natriuretic peptide (BNP) levels and in-hospital mortality risk. The vertical markson the loess line indicate density of the data.

B-type natriuretic peptide quartiles also predicted mortality in patients with LVEF <40%, LVEF ≥40%, and LVEF ≥50% as shown in Figure 2. These findings for BNP and mortality were independent of other major risk factors in patients with and without preserved systolic function. When the analysis was confined to patients with very low LVEF (<15%, n = 1,574) the median BNP was 1,539 pg/ml, and higher BNP remained predictive of mortality (Q1, BNP <865 pg/ml, 1.5% vs. Q4, BNP >2,830 pg/ml, 7.1%, p = 0.0005). Of 38,242 hospitalizations with documented BMI, there were 1,194 (3%) underweight, 12,018 (31%) healthy weight, 11,046 (29%) overweight, and 13,984 (37%) obese. There was a strong inverse relationship between BMI and median BNP levels: underweight 1,380 (interquartile range 732 to 2,890 pg/ml), healthy weight 1,217 (613 to 2,354), overweight 891 (480 to 1,740), and obese 555 (294 to 1,103), p < 0.0001. For each BMI category, except for the underweight group, BNP levels remained a significant univariate and multivariate predictor of in-hospital mortality. B-type natriuretic peptide levels were also independently predictive of mortality in unique patients with new onset heart failure (n = 11,707).

The BNP quartile groups also predicted other clinical outcomes, including the need for mechanical ventilation, length of stay, time in the intensive care unit, and percent hospitalization in the intensive care unit, as shown in Table 4.Patients in higher BNP quartiles were more likely to require mechanical ventilation and be hospitalized in the intensive care unit. These patients also had longer length of stays. Patients with higher BNP levels on admission were also less likely to be asymptomatic at hospital discharge.

Discussion

The ADHERE provides insights into the relationship among presenting characteristics, laboratories, and in-hospital outcomes in a broad population of patients recently hospitalized with acute decompensated HF. This analysis of >48,000 acute decompensated HF hospitalizations, in patients demographically and clinically similar to those seen in other large community- or Medicare-based evaluations (19,22), demonstrates that the risk of in-hospital mortality can be reliably estimated using BNP obtained on hospital admission. Overall, in-hospital mortality was 3.6%, but this mortality risk varied more than 3- to 4-fold on the basis of the patient’s initial BNP. B-type natriuretic peptide provides risk prediction independently of numerous other clinical and laboratory variables previously demonstrated to be predictive of in-hospital outcomes. This relationship between BNP and outcome persisted in hospitalized HF patients with both reduced and preserved systolic function and across BMI categories. Our findings confirm that BNP provides prognostic information among patients with cardiovascular disease, but they are the first to demonstrate this relationship with in-hospital mortality among patients hospitalized with acute decompensated HF.

Natriuretic peptides have been shown to predict prognosis in patients with acute coronary syndromes, stable coronary artery disease, chronic HF, and a variety of other medical conditions, as well as in community cohorts (6–11). There have been relatively few studies assessing the role of natriuretic peptide testing for predicting prognosis in patients presenting with acute decompensated HF. Harrison et al. (24) found that BNP levels measured in 325 patients presenting to the emergency department with dyspnea were predictive of cardiac events (cardiac death, emergency department visit, or admission for a cardiac cause) over the ensuing 6 months. The REDHOT (Rapid Emergency Department Heart Failure Outpatient Trial) was a 10-center study assessing the relationship between BNP levels and 90-day outcomes of patients presenting to the emergency department with shortness of breath (13). The BNP levels upon presentation were predictive of 90-day mortality rates, but multivariable analysis included only New York Heart Association functional class and disposition. In another analysis of 96 patients hospitalized with acute HF, admission NT-proBNP levels were not predictive of subsequent events (16). A larger report compared differences in NT-proBNP levels among 1,256 patients with and without acute HF and the relationship between NT-proBNP levels and HF symptoms in a pooled analysis of 3 studies and 1 registry cohort (18). The investigators found that in the acute HF subgroup, a presenting NT-proBNP concentration >5,180 pg/ml was predictive of death by 76 days. Finally, in a recent analysis of the PRIDE (ProBNP Investigation of Dyspnea in the Emergency Department) study of 599 patients who presented to the emergency department with dyspnea, it was observed that an elevated NT-proBNP concentration at presentation was predictive of death by 1 year after presentation, independent of other prognostic variables (17). These prior studies have mostly involved a mixed population of patients presenting with dyspnea, including patients not ultimately diagnosed as having heart failure; have involved relatively few study sites; have been inadequately powered; and as a result they have not adequately investigated whether natriuretic peptides are predictive of in-hospital mortality risk.

Because multiple risk factors can exist in the same patient, to be meaningful, analysis of the predictive value of a potential biomarker must consider its relationship to other prognostic factors and predictive models (20). As higher BNP levels are associated with other clinical presentation and laboratory variables that are indicative of higher risk, it could be speculated that BNP levels, although providing prognostic information in isolation, do not provide meaningful incremental risk prediction beyond traditional assessment. In this study, patients in the higher BNP quartiles were slightly older, and had a higher BUN, a lower admission SBP, and a lower LVEF than those in lower BNP quartiles. However, even after adjustment for multiple other prognostic factors previously identified by classification and regression tree analysis and/or logistic regression models as the most important risk factors for in-hospital mortality in acute decompensated HF and stratification for LV systolic function, the relationship between BNP and mortality persisted. This study demonstrates that assessment of admission BNP levels can provide prognostic information regarding in-hospital mortality in a broad population hospitalized with HF, which is incremental to clinical assessment and prior risk prediction models.

National guidelines for acute coronary syndromes recommend the use of the biomarkers cardiac troponin and BNP for prognosis and risk stratification (25). Current HF guidelines, however, recommend consideration of BNP testing solely for diagnostic purposes, and only in patients where the initial diagnosis is uncertain (26). These new findings suggest that assessment of presentation BNP levels in patients hospitalized with HF provides independent prognostic information regarding in-hospital mortality and other clinical outcomes and may be useful to stratify risk in HF patients. In light of the value of BNP and NT-proBNP testing in providing short-term and long-term prognostic information in patients presenting with acute decompensated HF, routine assessment of BNP or NT-proBNP levels may be considered (17,18). Unlike LVEF, which is frequently not available to clinicians for hours to days after hospital admission, BNP levels are generally available within 15 min to a few hours of presentation and are predictive of subsequent outcome in patients with both reduced and preserved systolic function. This incremental prognostic information provided by BNP has the potential to aid in medical decision making. Patients judged to be at higher risk may receive higher level monitoring and earlier, more intensive treatment for acute decompensated HF. Conversely, patients estimated to be at lower risk may receive lower level monitoring and be managed less intensively. However, prospective studies will be necessary to validate this hypothesis.

Conclusions

An elevated admission BNP level is a significant independent predictor of in-hospital mortality in acute HF. B-type natriuretic peptide level is predictive of in-hospital mortality in patients with either reduced or preserved LVEF independent of other clinical and laboratory variables. In light of the demonstration of incremental prognostic information, the BNP assay may be considered for inclusion as part of the assessment of patients presenting with acute decompensated HF. Further research will be necessary to determine whether patients with higher admission BNP will benefit from more intensive monitoring and aggressive treatment strategies.