Author + information
- Received February 13, 2013
- Revision received April 17, 2013
- Accepted April 24, 2013
- Published online August 1, 2013.
- Selim R. Krim, MD∗∗ ( )(, )
- Rey P. Vivo, MD†,‡,
- Nassim R. Krim, MD§,
- Feng Qian, MD, PhD⋮,
- Margueritte Cox, MS¶,
- Hector Ventura, MD∗,
- Adrian F. Hernandez, MD, MHS¶,
- Deepak L. Bhatt, MD, MPH# and
- Gregg C. Fonarow, MD∗∗
- ∗John Ochsner Heart and Vascular Institute, Ochsner Clinic Foundation, New Orleans, Louisiana
- †University of Texas Medical Branch, Galveston, Texas
- ‡Methodist DeBakey Heart and Vascular Center, Houston, Texas
- §Bronx Lebanon Hospital, Bronx, New York
- ⋮University at Albany-SUNY, Rensselaer, New York
- ¶Duke Clinical Research Institute, Durham, North Carolina
- #VA Boston Healthcare System, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts
- ∗∗Ahmanson-UCLA Cardiomyopathy Center, Ronald Reagan-UCLA Medical Center, Los Angeles, California
- ↵∗Reprint requests and correspondence:
Dr. Selim R. Krim, Division of Cardiology, John Ochsner Heart and Vascular Institute, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, Louisiana 70121.
Objectives This study sought to determine if there were differences in B-type natriuretic peptide (BNP) levels across racial/ethnic groups and in their association with quality of care and in-hospital outcomes among patients with heart failure (HF).
Background It remains unclear whether BNP levels and their associations with quality of care and prognosis vary by race/ethnicity among patients hospitalized with HF.
Methods Using Get With The Guidelines–Heart Failure (GWTG-HF), patient characteristics and BNP levels at admission were compared among 4 racial/ethnic populations: white, black, Hispanic, and Asian. The associations between BNP, quality of care, in-hospital mortality, and length of stay (LOS) across these groups were analyzed.
Results A total of 92,072 patients (65,037 white, 19,092 black, 6,747 Hispanic, and 1,196 Asian) from 264 hospitals were included. Median BNP levels were higher in Asian (1,066 pg/ml) and black (866 pg/ml) patients than in white (776 pg/ml) and Hispanic (737 pg/ml) patients, and race/ethnicity was independently associated with BNP levels (p < 0.0001). Irrespective of race/ethnicity, patients in higher BNP quartiles (Q3, Q4) were more likely to be older and male and have lower body mass index, reduced ejection fraction, and renal insufficiency, whereas those in the lowest quartile (Q1) were more likely to have diabetes. With some exceptions, there were no significant racial/ethnic differences in the association of BNP levels with performance measure adherence. In multivariate analysis, elevated BNP levels remained associated with longer LOS and increased mortality in all racial/ethnic groups.
Conclusions Asian and black patients with HF had higher BNP levels at admission compared with white and Hispanic patients. BNP levels at admission provided prognostic value for in-hospital mortality and hospital LOS irrespective of race/ethnicity.
The natriuretic peptides are counter-regulatory hormones involved in volume homeostasis and cardiovascular remodeling. B-type natriuretic peptide (BNP) levels have been shown to reliably facilitate diagnosis and predict prognosis in patients with acute and chronic heart failure (HF) (1–9). Elevated BNP levels at admission have been associated with a higher risk of in-hospital mortality as well as increased hospital and intensive care unit length of stay (LOS) (9). However, BNP levels may be influenced by a number of factors other than the severity of HF, including patient age (10,11), obesity (12,13), and renal insufficiency (14,15). Whether BNP levels are associated with race/ethnicity in patients with acute decompensated HF has not been well studied. Although limited data have suggested a potential interaction between race, BNP levels, and physicians' perception of HF severity (16), the association of BNP levels at admission with quality of care and outcomes by race/ethnicity in HF is unclear. Using data from the Get With The Guidelines–Heart Failure (GWTG-HF) registry, we aimed: 1) to compare BNP levels at admission among 4 racial/ethnic groups (white, black, Hispanic, and Asian) in patients hospitalized with HF; and 2) to determine if there were differences in the associations of BNP levels at admission with quality of care and in-hospital outcomes by racial/ethnic group.
Data collection and patient selection
The primary data source for this study was the GWTG-HF registry, an ongoing, national, voluntary program initiated in 2005 to improve adherence to quality-of-care guidelines for patients hospitalized with HF. Details and objectives of this American Heart Association–sponsored quality improvement program have previously been described (17). In summary, data including patient characteristics, medical history, medications, laboratory data, contraindications to treatment, inpatient care, outcomes, and hospital characteristics are collected using an interactive, Internet-based Patient Management Tool (Outcome Sciences, Inc., Cambridge, Massachusetts) by Outcome Sciences, Inc, the data collecting and coordinating center for GWTG. Data analysis was performed at the Duke Clinical Research Institute, which serves as the data analysis center and has institutional review board approval for analyzing the aggregate de-identified data for research purposes.
For this analysis, we included patients hospitalized with an episode of new or worsening HF as the primary reason for admission or with significant symptoms of HF that developed during hospitalization in which HF was the primary discharge diagnosis. Between January 2005 and July 2011, there were 155,316 patients admitted with HF from 299 hospitals fully participating in GWTG-HF. After excluding patients with no or missing BNP values (n = 56,838), BNP out of range (>5,001 pg/ml, n = 1,876), and race/ethnicity other than white, black, Asian, or Hispanic (n = 4,530), data on 92,072 patients from 264 hospitals were analyzed (Fig. 1). The primary analysis included a comparison of baseline characteristics, BNP levels at admission, and outcomes among the 4 racial/ethnic groups. Subsequent analysis was performed by dividing patients into both BNP quartiles and log-transformed BNP. The characteristics of patients and in-hospital outcomes of patients with and without BNP measured overall and for each race/ethnic group are shown in Online Tables 1 to 5.
Variable definition, performance measures, and outcomes
BNP values were usually measured at the time of presentation but no later than within 24 h of admission. Although the GWTG-HF registry includes both BNP and NT-proBNP, only BNP was used in our analysis because most of the enrolled sites used the BNP assay. Race was recorded as part of a multiple-choice data entry tool (i.e., white, black, Asian, American Indian/Alaska Native, and Native Hawaiian/Pacific Islander). A separate data element for Hispanic ethnicity (i.e., yes vs. no/not documented) was also applied. The following performance measures were included in this study: assessment of left ventricular (LV) function, prescription of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs), use of beta-blockers, counseling for smoking cessation, and discharge instructions. In-hospital outcomes evaluated were in-hospital mortality and LOS.
Baseline patient characteristics were compared among groups first by BNP quartiles and then by log-transformed BNP. Median values with interquartile ranges (IQRs) were used to describe continuous variables, and numbers and percentages were reported for categorical variables. Chi-square tests were used to test for significant differences in categorical variables, and Wilcoxon rank sum tests were used for continuous variables. The association between BNP levels, performance measures, and clinical outcomes was assessed using multivariable generalized estimating equation logistic regression models, which accounted for the correlation of data within hospitals (18). Variables in the model included age, sex, body mass index (BMI), blood urea nitrogen level, serum creatinine level, serum sodium level, systolic blood pressure, heart rate, ischemic history, ejection fraction, history of anemia, stroke/transient ischemic attack, diabetes, hyperlipidemia, hypertension, chronic obstructive pulmonary disease/asthma, peripheral arterial disease, renal insufficiency, smoking, geographic region, teaching hospital, and number of beds. Patients with sex and BMI coded as missing were excluded from the multivariable analysis. In general, overall missing rates for variables included in the model were less than 7%, with the exception of BMI, which was approximately 12%. Missing values for continuous variables were imputed to the overall median value. Because of higher missing rates for BMI, BMI was not imputed. Medical history variables were imputed to the most likely category (“no history”). Hospital characteristics (i.e., region, teaching hospital, and number of beds) were not imputed. A relationship between in-hospital mortality in each racial/ethnic group and BNP as a continuous variable was also examined using locally weighted smoother regression scatterplots (LOESS). The plots were created using the Hmisc package R version 2.12.0 (FE Harrell, Department of Biostatistics, Vanderbilt University, Nashville, Tennessee). Because of the small sample size of the Asian group, models for LOS and mortality were fit using the entire cohort. Interaction terms for log-transformed BNP by race were also included in the model to compare log-transformed BNP among racial groups. Linear regression using generalized estimating equations was used to explore whether race/ethnicity was associated with BNP and log-transformed BNP at admission. This model also adjusted for demographics, baseline patient characteristics, medical history, and hospital characteristics as described in the preceding text.
All tests were 2 sided, and p values <0.05 were considered statistically significant. All analyses were performed using SAS version 9.2 (SAS Institute, Cary, North Carolina).
A total of 92,072 patients (65,037 white, 19,092 black, 6,747 Hispanic, and 1,196 Asian) comprised the final study population. Baseline patient characteristics are presented in Table 1. Overall, the median age was 75 years. White (median age: 78 years) and Asian (median age: 75 years) patients were more likely to be older than black (median age: 63 years) and Hispanic (median age: 70 years) patients. Ischemic etiology was predominant across all groups except black patients. Median BNP levels were significantly higher in Asian (1,066 pg/ml) and black (866 pg/ml) patients than in white (776 pg/ml) and Hispanic (737 pg/ml) patients (Table 1). Levels of BNP by quartile for each racial/ethnic group are shown in Table 2. With the exception of Asian patients, patients in higher BNP quartiles (Q4) were more likely to be older than those in lower quartiles (Q1) (Online Tables 6 to 9). Additionally, patients in higher quartiles were more likely to be male and have lower BMI, ischemic etiology, lower LV ejection fraction, and renal insufficiency, whereas patients in lower quartiles were more likely to have diabetes and hyperlipidemia. Table 3 shows the predicted (mean) value of log-transformed BNP for each racial/ethnic group (relative to white patients) and demonstrates that race/ethnicity was associated with BNP levels at admission independent of other patient and hospital characteristics.
Table 4 displays adherence to performance measures stratified by BNP quartiles. Overall, there were some differences in quality of care between patients in higher BNP quartiles when compared with lower BNP quartiles, with some variability among racial/ethnic groups. Specifically, in unadjusted analyses, white and black patients, but not Hispanic or Asian patients, in higher BNP quartiles were more likely to receive ACEI/ARB therapy when compared with patients in lower BNP quartiles. Also, black patients, but not white, Hispanic, or Asian patients, in higher BNP quartiles were more likely to receive beta-blocker therapy. Interestingly, white and Hispanic patients in higher BNP quartiles were less likely to be given discharge instructions. After multivariate analysis, white and black patients with higher BNP levels were more likely than patients with lower BNP levels to receive discharge instructions and to have an evaluation of their LV function, while no significant difference was found among Hispanic or Asian patients (Online Tables 10 and 11).
In-hospital mortality and LOS
The association between BNP quartiles/log-transformed BNP and outcomes are summarized in Tables 5 and 6 and in Figure 2. In unadjusted analyses, higher BNP quartiles were associated with higher in-hospital mortality in all groups except for Asian patients (white patients: Q4 5% vs. Q1 2%, p < 0.0001; black patients: Q4 2.2% vs. Q1 1.5%, p = 0.004; Asian patients: Q4 3.3% vs. Q1 5%, p = 0.38; Hispanic patients: Q4 3.6% vs. Q1 1.5%, p < 0.0001). Similarly, patients with higher BNP levels were more likely to have longer LOS (>4 days) regardless of race/ethnicity. After adjusting for BMI and other patient characteristics, BNP remained associated with longer LOS in all racial/ethnic groups (white patients: OR: 1.15, 95% CI: 1.12 to 1.17, p < 0.0001; black patients: OR: 1.15, 95% CI: 1.12 to 1.18, p < 0.0001; Asian patients: OR: 1.19, 95% CI: 1.07 to 1.31, p = 0.0005; Hispanic patients: OR: 1.20, 95% CI: 1.14 to 1.25, p < 0.0001). BNP levels were also independently associated with increased mortality in all subgroups (Table 6).
This large study of 92,072 patients with HF is among the first to explore the association between race/ethnicity, BNP levels at admission, quality of care, and outcomes. Our results offer some important findings. First, BNP levels at admission were higher in Asian and black patients than in white and Hispanic patients enrolled in GWTG-HF. Second, patients in higher BNP quartiles were more likely to be older and male and to have lower BMI, ischemic etiology, systolic dysfunction (LV ejection fraction <40%), and renal insufficiency regardless of race/ethnicity. Third, with few exceptions, the association between BNP levels and adherence to HF performance measures did not vary significantly across race/ethnicity. Finally, higher BNP levels correlated with longer hospital stay and in-hospital mortality irrespective of racial/ethnic group.
Similar to results from the ADHERE (Acute Decompensated Heart Failure National Registry) study (9), we found that patients in higher BNP quartiles were more likely to be older and male and to have systolic dysfunction and lower BMI, all known strong prognostic markers in patients with HF. Our study also showed that patients in higher BNP quartiles were less likely to have diabetes, a finding that may likely be explained by the known inverse correlation between BNP levels and obesity (12,13). Concordant with previous findings indicating that black patients have higher BNP levels at admission than white patients (11,16), our analysis provides additional insight that there is a significant variation in baseline BNP levels among the 4 racial/ethnic subgroups independent of other patient and hospital characteristics. Previous data have suggested that variation in plasma BNP levels may be attributed to genetic factors (19). In our study, the higher BNP levels seen in black patients may be explained by the higher rate of renal insufficiency, higher median systolic and diastolic pressure, and higher rate of lower median ejection fraction; however, even after adjusting for these variables, differences in BNP were noted. Similarly, the higher BNP levels observed in Asian patients may be related to their older age, male predominance, lower BMI, and higher rates of renal insufficiency (10–15), although race/ethnicity remained independently associated with BNP even after adjustment for these variables.
Data on the association between BNP and quality of HF care remain limited. A report from the registry to IMPROVE-HF (Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting) (20) showed that ambulatory patients with HF who had higher BNP levels were less likely to be treated with ACEI/ARB therapy or aldosterone antagonists. With some exceptions, we also found no significant association between BNP levels and adherence to HF performance measures across different racial/ethnic populations. This lack of correlation may imply an overall high quality of care implemented by participating GWTG-HF hospitals. As a counterpoint, this finding may indicate a mismatch between higher-risk and evidence-based interventions. Nevertheless, we found that higher BNP levels were associated with higher rates of discharge instruction delivery and LV function evaluation in white and black patients but not in Hispanic or Asian patients.
Prior studies examining the relationship between BNP, race, and outcome have been limited to white and black populations (11,16). The Breathing Not Properly Multinational Study (11), an analysis of 1,586 patients with acute dyspnea, found that differences in BNP levels between white and black patients were small. Data from the REDHOT (Rapid Emergency Department Heart Failure Outpatient Trial) study (16) demonstrated that while there were variations in BNP levels between white and black patients, there were no significant differences in 90-day clinical outcomes. With regard to in-hospital mortality by BNP levels at admission, although our unadjusted analysis showed differences across BNP quartiles between race/ethnic subgroups, the adjusted ORs (except for white patients) were not statistically significant in other subgroups (Table 5). Because there was no statistically significant heterogeneity for in-hospital mortality by BNP levels for the race/ethnic groups, our data would suggest that any individual group differences are not statistically important. Furthermore, after multivariate adjustment in the present study, we found a statistically significant association between BNP and LOS and in-hospital mortality in all racial/ethnic groups.
Some limitations to our study need to be mentioned. First, because of the retrospective nature of our study and because BNP levels were not obtained in all patients, there is a potential for bias. The quality of chart review and data collection relied on the accuracy and completeness of documentation and abstraction; therefore, missing documentation of contraindications to guideline-recommended therapy may have influenced our results. Second, data on race and ethnicity were self-reported and collected by administrative staff or admitting providers. Moreover, data subcategorized by Asian and Hispanic nationality, unavailable in the registry, may reveal other differences in clinical characteristics, access to care, and outcomes. Third, only BNP was included in our analysis because it was the most commonly used biomarker among participating hospitals. The applicability of these results with NT-proBNP needs to be clarified. Our findings were based on results from various commercially available BNP assays rather than from a single central core laboratory. Furthermore, we only included the BNP level at admission without documentation for serial or discharge BNP levels. Fourth, our results can only be interpreted among patients hospitalized with HF. Fifth, data on readmission rates and long-term outcomes were lacking. Sixth, our results cannot be extrapolated to non-GWTG hospitals, where adherence to HF measures and outcomes of patients with HF may be different. Finally, because of a low sample size, our study was not sufficiently powered to adequately analyze the correlation of BNP with mortality in Asian patients; therefore, further study of the prognostic value of BNP in this racial/ethnic group is needed. Conversely, because of the large study population, some differences that reached statistical significance may not necessarily represent clinical relevance.
Our study shows that among GWTG-HF patients, BNP levels differed by race/ethnic group independent of other patient and hospital characteristics. Specifically, Asian and black patients had higher BNP levels at admission than white and Hispanic patients. With some exceptions, there were no significant racial/ethnic differences in the association of BNP and adherence to HF performance measures. Higher BNP levels correlated with longer hospital stay and in-hospital mortality irrespective of racial/ethnic group, suggesting that race/ethnicity may not significantly affect the prognostic value of BNP among patients hospitalized with HF.
The Get With The Guidelines–Heart Failure (GWTG-HF) program is provided by the American Heart Association. GWTG-HF has been funded in the past through support from Medtronic, GlaxoSmithKline, Ortho-McNeil, and the American Heart Association Pharmaceutical Roundtable. Dr. Ventura is a member of the speakers' bureau for Otsuka and Actelion. Dr. Hernandez has received research grants from Bristol-Myers Squibb, Johnson & Johnson, and Medtronic; and has served as a consultant to Amgen, AstraZeneca, Bristol-Myers Squibb, Corthera, and Janssen. Dr. Bhatt is an advisory board member for Medscape Cardiology; serves on the board of directors of the Boston VA Research Institute and Society of Chest Pain Centers; is chair of the American Heart Association Get With The Guidelines Science Subcommittee; has received honoraria from the American College of Cardiology (editor, clinical trials, Cardiosource), Duke Clinical Research Institute (clinical trial steering committees), Slack Publications (chief medical editor, Cardiology Today Intervention), and WebMD (CME steering committees); is senior associate editor of Journal of Invasive Cardiology; has received research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi-Aventis, and The Medicines Company; and has performed unfunded research for FlowCo, PLx Pharma, and Takeda. Dr. Fonarow is former chair of the American Heart Association Get With the Guidelines Steering Committee; has received research grants from the National Heart, Lung, and Blood Institute; has received honoraria from Medtronic; and is a consultant for Novartis and Pfizer. All other authors have reported that they have no relationships relevant to the content of this paper to disclose. John R. Teerlink, MD, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- angiotensin-converting enzyme inhibitor
- angiotensin receptor blocker
- body mass index
- B-type natriuretic peptide
- heart failure
- interquartile range
- left ventricular
- N-terminal pro-brain natriuretic peptide
- Received February 13, 2013.
- Revision received April 17, 2013.
- Accepted April 24, 2013.
- American College of Cardiology Foundation
- Cowrie M.R.,
- Jourdain P.,
- Maisel A.S.,
- et al.
- Anand I.S.,
- Fisher L.D.,
- Chiang Y.T.,
- et al.
- Bettencourt P.,
- Azevedo A.,
- Pimenta J.,
- et al.
- Gustafsson F.,
- Steensgaard-Hansen F.,
- Badskjaer J.,
- et al.
- Fonarow G.C.,
- Peacock W.F.,
- Phillips C.O.,
- Givertz M.M.,
- Lopatin M.,
- for the ADHERE Scientific Advisory Committee and Investigators
- Redfield M.M.,
- Rodeheffer R.J.,
- Jacobsen S.J.,
- et al.
- Wang T.J.,
- Larson M.G.,
- Levy D.,
- et al.
- Horwich T.B.,
- Hamilton M.A.,
- Fonarow G.C.
- Austin W.J.,
- Bhalla V.,
- Hernandez-Arce I.,
- et al.
- Wang T.J.,
- Larson M.G.,
- Levy D.,
- et al.
- Ambrosy A.P.,
- Fonarow G.C.,
- Albert N.M.,
- et al.