Low prevalence of B-type natriuretic peptide levels <100 pg/mL in patients with heart failure at hospital discharge
Article Outline
Background
In patients with acute heart failure (HF) presenting at the emergency department, a B-type natriuretic peptide (BNP) level <100 pg/mL was found in only 10% of the patients. However, in a more stable outpatient HF population from another study, a BNP level <100 pg/mL was found in as many as 21% of the patients. Therefore, we aimed to investigate the prevalence and characteristics of stabilized patients with BNP levels <100 pg/mL before discharge after admission for decompensated heart failure HF.
Methods
We investigated 601 patients with HF who were part of a large-scale multicenter study in The Netherlands. All patients had been admitted for decompensated HF, and their BNP levels were measured before discharge when they had been clinically stabilized. Clinical characteristics of patients with BNP levels <100 and ≥100 pg/mL were compared.
Results
Patients were 70 ± 12 years old, 61% were men, and mean left ventricular ejection fraction was 0.34 ± 0.14. Of these patients, 10% had BNP levels <100 pg/mL. Patients with a BNP level <100 pg/mL were similar in age and sex but had higher left ventricular ejection fraction (0.41 ± 0.14 vs 0.33 ± 0.13, P < .001), body mass index, and hemoglobin and hematocrit concentrations compared with those with BNP levels ≥100 pg/mL.
Conclusions
In clinically stable patients with a recent admission for decompensated HF, only 10% had BNP levels ≥100 pg/mL. These patients with low BNP levels seemed to have less severe HF and more frequently had preserved systolic function compared with patients with BNP levels ≥100 pg/mL.
B-type Natriuretic Peptide (BNP) is increasingly used in the diagnosis and prognosis of heart failure (HF).1, 2, 3 In addition, BNP can be used as a discharge criterion and to monitor treatment.4, 5 A BNP value of 100 pg/mL is considered the optimal value in the diagnosis or exclusion of HF in acute dyspneic patients at the emergency department.2 In these patients, a BNP cut-off value of 100 pg/mL had a sensitivity of 90%, which means that only 10% of patients with HF had BNP plasma levels <100 pg/mL. When the same cut-off value was used in a stable outpatient systolic HF population, classified as NYHA functional class II to III, as many as 21% of patients had BNP levels <100 pg/mL,6 which might suggest that the prevalence of patients with BNP levels below this cutoff value is much higher than 10% in stable patients with HF at discharge. However, the prevalence of BNP levels <100 pg/mL in clinically stable hospitalized patients remains unknown. Hence, we investigated the prevalence and characteristics of patients with BNP levels <100 pg/mL classified in New York Heart Association (NYHA) class II to IV before discharge after admission for HF.
Methods
Study population
All patients were included in a multicenter HF trial conducted in The Netherlands (NHF-COACH).7 All these sites (n = 17) were experienced HF centers. Patients were included in NHF-COACH if they were admitted for decompensated HF (NYHA II to IV), with HF as the primary diagnosis. Furthermore, patients were required to have evidence of structural underlying heart disease and had to be at least 18 years of age. Reasons for exclusion were concurrent inclusion in a study requiring additional visits to research health care personnel; restrictions that make the patient unable to fill in the data collection forms; invasive intervention within the last 6 months (percutaneous transluminal coronary angioplasty, coronary artery bypass graft, HTX, valve replacement) or planned during the next 3 months; and ongoing evaluation for heart transplantation. The design of the study has been described in detail elsewhere.7 In short, NHF-COACH is a randomized controlled trial investigating the effect of education and counseling on readmission for HF and mortality. Of the 1050 patients included in the NHF-COACH, 601 patients had BNP plasma levels available at baseline. Main reasons for missing BNP data were no Triage BNP meter available (in 5 of 17 clinics; n = 324), unplanned hospital discharge (n = 75), or death during admission (n = 20). No BNP levels were available at admission, and the investigators and patients of the present study were blinded to BNP results at discharge.
The study was approved by a central ethical committee, and all patients provided informed written consent.
B-type natriuretic peptide measurement
Blood was collected before discharge between 8:00 am and 4:00 pm after patients had been clinically stabilized and were recovered well enough to go home. All patients went home at the planned day of discharge. Five milliliters of whole blood was taken from an antecubital vein and collected into tubes containing potassium EDTA (1 mg/mL blood) when patients were in a supine position. Within 4 hours after blood collection, BNP plasma levels were determined using a fluorescence immunoassay kit (Triage, Biosite Incorporated, San Diego, CA). Details on the system provided by the manufacturer indicated that the analytical sensitivity of the assay is <5.0 pg/mL. The system has been validated in early studies.8, 9 The measurable range of the BNP assays was 5.0 to 5000.0 pg/mL.
Renal function
Serum creatinine was determined from the blood draw before discharge in the local laboratory at each center. Estimated glomerular filtration rates were calculated using the Levey–modified Modification of Diet in Renal Disease formula10:
Additional demographic and clinical data were collected by chart review.
Statistical analysis
Differences in clinical characteristics between patients with BNP plasma levels <100 and ≥100 pg/mL were tested using the Mann-Whitney U test or independent samples t tests. Outcomes were considered statistically significant at P < .05. Values are presented as means ±SD except when stated otherwise.
Results
Study population
Demographic and clinical characteristics of the 601 discharged patients are presented in Table I. Mean age of the patients was 70 (±12) years, and more than half of the population were men (61%) and had a nonischemic etiology for HF (62%). At admission, patients were classified as NYHA functional class II (6%), III (53%), or IV (41%) and were on medical therapy including diuretics (57%), angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (52%), β-blockers (39%), and spironolactone (16%). At discharge, patients were classified as NYHA functional class II (52%), III (45%), or IV (3%) and were on medical therapy including diuretics (95%), ACE inhibitors/angiotensin receptor blockers (84%), β-blockers (61%), and spironolactone (50%).
Table I. Patient characteristics divided by BNP levels
| Total (n = 601) | BNP level <100 pg/mL (n = 60) | BNP level ≥100 pg/mL (n = 541) | P | |
|---|---|---|---|---|
| Age (y) | 70 ± 12 | 69 ± 11 | 70 ± 12 | .29 |
| Sex (m) | 61% | 58% | 61% | .65 |
| HF cause | ||||
 Ischemic | 38% | 30% | 39% | .18 |
| Nonischemic | 62% | 70% | 61% | .18 |
| LVEF | 0.34 ± 0.14 | 0.41 ± 0.14 | 0.33 ± 0.13 | <.001 |
| Comorbidities | ||||
| Hypertension | 34% | 47% | 33% | .03 |
| COPD/asthma | 28% | 30% | 28% | .71 |
| Diabetes (type1 or 2) | 28% | 27% | 28% | .84 |
| Renal diseases | 7% | 7% | 7% | 1.00 |
| BMI (kg/m2) | 26 ± 5 | 30 ± 6 | 26 ± 5 | <.001 |
| X-thorax during admission | ||||
| Pulmonal congestion | 69% | 57% | 70% | .04 |
| CT ratio (n = 158) | 0.56 ± 0.08 | 0.53 ± 0.15 | 0.57 ± 0.06 | .05 |
| Crepitating during admission | 87% | 89% | 87% | .76 |
| Duration of HF symptoms (y) | 2.7 ± 4.2 | 2.7 ± 4.0 | 2.7 ± 4.2 | .93 |
| Duration HF admission (d) | 13 ± 11 | 13 ± 8 | 13 ± 11 | .55 |
| Medication at admission | ||||
| Diuretics | 57% | 63% | 56% | .29 |
| ACE/ARB | 52% | 60% | 51% | .19 |
| β-blockers | 39% | 38% | 39% | .96 |
| Spironolacton | 16% | 22% | 15% | .18 |
| Medication at discharge | ||||
| Diuretics | 95% | 92% | 95% | .21 |
| ACE/ARB | 84% | 83% | 84% | .94 |
| β-blockers | 61% | 48% | 63% | .03 |
| Spironolacton | 50% | 50% | 50% | .97 |
| ECG measurements at discharge | ||||
| Sinus rhythm | 56% | 67% | 55% | .08 |
| AF/flutter | 34% | 30% | 35% | .48 |
| HR (beat/min) | 74 ± 13 | 76 ± 13 | 74 ± 13 | .42 |
| Laboratory values at discharge | ||||
| BNP (median [interquartile range]) (pg/mL) | 492 (223-952) | 55 (37-79) | 530 (294-1060) | <.001 |
| Hb (mmol/L) | 8.2 ± 1.2 | 9.0 ± 1.1 | 8.2 ± 1.1 | <.001 |
| Ht (1 per L) | 0.40 ± 0.05 | 0.43 ± 0.05 | 0.40 ± 0.05 | <.01 |
| eGFR (mL/min per 1.73 m2) | 56 ± 21 | 57 ± 18 | 55 ± 22 | .56 |
| Blood pressure at discharge (mm Hg) | ||||
| Systolic | 119 ± 22 | 124 ± 22 | 118 ± 21 | .05 |
| Diastolic | 69 ± 12 | 73 ± 13 | 68 ± 12 | .03 |
| Pulse pressure | 50 ± 17 | 51 ± 17 | 50 ± 17 | .48 |
| NYHA at admission (II, III, IV) | 6%, 53%, 41% | 2%, 68%, 30% | 7%, 51%, 42% | .23 |
| NYHA at discharge (II, III, IV) | 52%, 45%, 3% | 48%, 50%, 2% | 53%, 44%, 3% | .62 |
Prevalence of low BNP levels at discharge after HF hospitalization
Of the 601 patients with HF, 60 patients (10%) had BNP plasma levels <100 pg/mL. Of these 60 patients, 44 patients (7% of the total population) and 28 patients (5% of the total population) had BNP levels <75 pg/mL and <50 pg/mL, respectively (Figure 1).
Figure 1.
B-type natriuretic peptide plasma levels (n = 601).
Comparison of patients with BNP <100 and ≥100 pg/mL
The median and interquartile range of BNP values in the group of patients with BNP <100 and ≥100 pg/mL were 55 (37-79) and 530 (294-1060), respectively (Table I). Patients with BNP levels <100 pg/mL showed less pulmonary congestion during hospital admission, compared with patients with high BNP levels (57% vs 70%, respectively; P = .04). At discharge, these patients had a significantly higher left ventricular ejection fraction (LVEF) (0.41 ± 0.14 vs 0.33 ± 0.13; P < .001) and diastolic blood pressure (73 ± 13 mm Hg vs 68 ± 12 mm Hg; P = .02) and a significantly higher prevalence of hypertension (47% vs 33%; P = .02) than patients with BNP levels ≥ 100 pg/mL. Furthermore, at discharge, body mass index (BMI) (30 ± 6 vs 26 ± 5; P < .001), hemoglobin (9.0 ± 1.1 vs 8.2 ± 1.1; P < .001), and hematocrit (0.43 ± 0.05 vs 0.40 ± 0.05; P < .01) were significantly higher in patients with low BNP levels compared with patients with high BNP levels. Moreover, patients with low BNP levels less often had received β-blockers at discharge (48% vs 63%; P = .03), compared with patients with high BNP levels. Other variables were not significantly different between the 2 groups (Table I).
Discussion
The major finding of the present study is that only 10% of clinically stabilized hospitalized patients with HF had predischarge BNP plasma levels <100 pg/mL.
In patients with acute dyspnea, Maisel et al2 showed a sensitivity of 90% for a BNP cut-off value of 100 pg/mL to diagnose HF, and Morrison et al11 showed a sensitivity of 86% for a BNP value of 94 pg/mL to differentiate HF from pulmonary disease. In other words, in these studies, 10% and 14% of patients with HF had BNP plasma levels <100 and 94 pg/mL, respectively.
In an outpatient clinic setting, Tang et al6 found that as much as 21% of chronic symptomatic systolic patients with HF had BNP levels <100 pg/mL. Recently, a low prevalence of low BNP levels was shown in a systematic review that mainly described studies on acute dyspnea and outpatient clinic patients with HF. However, most studies described in this review showed the highest diagnostic accuracy to differentiate between dyspnea due to HF and dyspnea due to other pathologies for a cutoff value of 52 pg/mL.12 Because BNP is related to the severity of HF,13 it is conceivable that BNP plasma levels are higher in patients with HF during acute dyspnea, compared with an outpatient clinic setting. In addition, BNP levels are probably higher in acute dyspneic patients with HF, compared with “dry BNP levels” in stabilized patients with HF.14 Therefore, the 10% of patients with HF with BNP levels <100 pg/mL who were found in the present study are lower than expected, based on previous literature.14 When the cutoff values of 75 pg/mL and 50 pg/mL were used, 7% and 5% of the patients were found to have BNP levels below these cut-off values, respectively. This finding shows that within the group of patients with BNP <100 pg/mL, the distribution of BNP levels was normal, indicating that in this group, no majority exists with “healthy” BNP levels of <20 pg/mL.15
Tang et al6 showed that patients with BNP levels <100 pg/mL were more likely to be younger, to be women, and to have a nonischemic etiology, better-preserved cardiac and renal function, and less atrial fibrillation, as compared with patients with BNP levels >100 pg/mL. The same differences between the groups were found in the present study (Table I), although of these variables, only LVEF was statistically significant. This indicates a specific profile of patients with BNP plasma levels <100 pg/mL. The differences between patients with high and low BNP levels in the current population suggest that patients with BNP <100 pg/mL had less severe HF and more often had HF with preserved systolic function.
Moreover, we found significantly higher BMIs in the low BNP group, confirming data recently published that have shown that obesity is related to lower BNP values.16, 17 There are 2 explanations for this consistent finding. First, natriuretic peptide clearance receptors are abundant in adipose tissue, suggesting that adipocytes participate in the removal of natriuretic peptides from the circulation.18 A second explanation of lower BNP plasma levels in obese patients may be an impaired natriuretic peptide secretion. In isolated obese Zucker rat hearts, an impaired signal cascade myocardial protein kinase C–MAP inase–natriuretic peptide secretion was shown, as compared with lean rat hearts.19 In another study in young, healthy, normotensive obese subjects, an impaired natriuretic peptide secretion was shown in response to saline load.20
Logeart et al showed that patients with a decrease in BNP plasma levels during HF admission had a lower risk on events after discharge, compared with patients with unchanged or increased BNP levels during admission.21 Therefore, the authors recommend a “decrease of BNP approach” for clinical practice. The present results, however, indicate that a goal of decreasing BNP levels during HF admission <100 pg/mL is not realistic for most patients.
Altogether, the 10% of patients with heart failure who were found to have low BNP levels at discharge in the present study is a remarkably low percentage when taking into account that 21% of stable outpatient clinic patients had low BNP levels. This finding adds value to the use of BNP in clinical practice in patients recently admitted for HF and extends the low prevalence of normal BNP levels from acute dyspneic patients2 to stabilized inhospital HF patients.
Limitations
The present study was limited by its cross-sectional design. B-type natriuretic peptide plasma levels at hospital admission and postdischarge outcomes would have added to the importance of the study. However, an evaluation of the BNP value of 100 pg/mL at hospital discharge adds important knowledge for clinical practice because this value is increasingly used.
Conclusions
The present study demonstrated that 10% of patients with a recent admission for decompensated HF have BNP plasma levels 100 pg/mL. These patients seem to have less severe HF and more often have HF with preserved systolic function.
We are grateful to Biosite Incorporated (San Diego, CA) for providing Triage BNP assay kits and to Novartis (Arnhem, The Netherlands) for an unrestricted grant to invest in Triage BNP meters.
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The NHF-COACH study is financially supported by the Netherlands Heart Foundation (Grant 2000Z003). Prof van Veldhuisen is an established investigator of the Netherlands Heart Foundation (Grant D97.017).
PII: S0002-8703(06)00007-X
doi:10.1016/j.ahj.2005.12.012
© 2006 Mosby, Inc. All rights reserved.
