The value of BNP plasma levels in very old persons with chronic peripheral edema
Joël BELMIN (1,2)
Cristiano DONADIO 1)
Witold JARZEBOWSKI (1)
Kamran GENRANMAYEH (1)
Lucie VALEMBOIS (1)
Carmelo LAFUENTE-LAFUENTE (1, 2)
(1) Hôpitaux Universitaires Pitié-Salpêtrière-Charles Foix, Hôpital Charles Foix, 94200 Ivry-sur-Seine, France
(2) Sorbonne Université (UPMC), 75013 Paris, France
Corresponding author:
Prof. Joël BELMIN, Service de gériatrie, Hôpital Charles Foix, 7 avenue de la République, 94200 Ivry-sur-Seine, France
j.belmin@aphp.fr tel: + 331 49 59 45 65 fax: +331 49 59 43 79
Keywords: chronic heart failure, elderly, BNP, brain natriuretic peptide, chronic peripheral edema
Abstract
Background: Chronic peripheral edema (CPE) is frequent in old patients and very often results from multiple causes.
Aims: To investigate if BNP plasma dosage helped diagnose etiologies of CPE.
Methods: Cross-sectional observational study conducted in geriatric hospital wards (intermediate and long-term care) on consecutive in-hospital patients > 75 years having CPE and no dyspnea. From medical history, physical examination, routine biological tests and chest radiography, two investigators determined the etiologies of edema with special attention to recognize chronic heart failure (CHF). This reference diagnosis was compared to the clinical diagnosis mentioned in the medical chart. BNP plasma levels were measured soon after the investigators visit.
Results: Among the 141 patients (113 women and 28 men) aged 86 +/- 6 years, a single cause was identified in 53 (38%), and multiple causes in 84 (60%). Main causes were venous insufficiency (69%), CHF (43%), hypoprotidemia (38%) and drug induced edema (26%). CHF was frequently misdiagnosed by attending clinicians, missed in 18 cases and wrongly diagnosed in 14. BNP was significantly higher in patients with CHF than in those without (median and interquartile range: 490 [324-954] and 137 [79-203] pg/mL respectively, p<0.0001). ROC curve showed that the level of 274 pg/mL was appropriate to diagnose CHF with specificity of 0.89 and sensitivity of 0.82. BNP level above this cut-off was
significantly and independently associated to the diagnosis of CHF.
Conclusion: CHF is frequently misdiagnosed in old patients with CPE and BNP dosage helped to improve diagnosis of this condition and identify CHF.
Chronic peripheral edema (CPE) is frequent in old patients and very often results from multiple mechanisms, including elevated peripheral or central venous pressure, decreased oncotic plasma pressure, increased capillary permeability related to drugs or to vascular inflammation or damage (1, 2). The diseases responsible for CPE are numerous, and the appropriate diagnosis is often a challenging task for clinicians (3, 4, 5, 6, 7, 8). In very old patients, the diagnosis is more difficult due to several reasons (9). First, multiple
etiologies are often encountered in the same patient due to the high prevalence of chronic diseases which make the diagnosis more complex (9); the diagnosis of heart failure is often more difficult due to reduced physical activity and/or atypical symptoms; chronic venous disease is very frequent and often lead to miss another concomitant etiology of CPE.
Appropriate management of CPE mainly depends on the etiology of edema. The identification of heart failure in patients with CPE is of crucial importance (4, 5, 10).
Among patients with CPE, mortality was three fold higher in those with heart failure than in those without (10). Heart failure requires an appropriate treatment which is able improve symptoms and prognosis.
Brain natriuretic peptide (BNP) determination was found to help the diagnosis of heart failure in patients with acute dyspnea (11, 12, 13) including elder persons (14) and its dosage is becoming widely available. We hypothesized that in very old patients, BNP dosage could help the clinician for determining etiologies of CPE not associated with dyspnea.
Methods
Design and patients
This prospective observational cross-sectional study was conducted in 4 geriatric wards of a French hospital (Hôpital Charles Foix, Ivry-sur-Seine), in intermediate care and long term care settings. Consecutive patients were included if they were 75 years or older, had
peripheral edema for more than 15 days, had no dyspnea or documented acute heart failure and were not in end-of-life situation.
For each patient, we recorded from the medical chart the etiologies of edema determined by the physician responsible for the patient care. We also discussed with him/her to record additional information about etiologies of CPE not mentioned in the medical chart. In the following this referred to the “clinical diagnosis”.
Reference diagnosis of CPE etiologies
Two investigators (a geriatrician and a cardiologist) developed a systematic approach to determine etiologies of CPE derived from literature (4,5). They searched history of impaired exercise tolerance, dyspnea, heart, pulmonary or liver disease, venous thromboembolic disease. They examined patients to search for pulmonary crackles, hepatojugular reflux or jugular distension, varicose veins (in upright position), lower limb hemosiderin skin deposits or venous ulcers, skin thickening or changes. They also recorded drugs, realized ECG and analyzed it to search for repolarization abnormalities, atrial fibrillation and signs of prior myocardial infarction. The most recent chest radiograph of the medical chart was analyzed to search for pleural effusion, alveolar or interstitial pulmonary edema and to calculate cardiothoracic index. Recent blood biochemical analysis for creatinine, TSH, proteins, albumin available in the medical records were also provided, with the exception of brain natriuretic peptide (BNP) if it had been measured before.
Echocardiography and venous ultrasound were performed at the discretion of the attending clinician and, when available, were also considered by the investigators. Using all these elements, each investigator separately determined the etiologies of edema for each patient. The diagnosis of heart failure was based on the 2008 guidelines of the European Society of Cardiology for heart failure (15). Symptoms and signs compatible with heart failure were defined as: (i) breathlessness, graded as New York Heart Association (NYHA) class II, III, or IV; (ii) moderate edema (up to the knees bilaterally); or (iii) mild edema (confined to the ankles) + one other clinical sign (see below); (iv) mild edema and taking at least furosemide 40 mg (or equivalent) per day; or (v) two or more other signs [raised
jugular venous pressure (JVP), lung crackles, respiratory rate >20/min, third heart sound].
In cases where the diagnosis remains uncertain, the response to treatment directed towards heart failure was taken into account. The diagnosis of chronic venous disease was retained if patient had a history of lower limb venous thrombosis or venous ulcer,
extensive varicose veins and skin hemosiderin deposit and/or ultrasound examination showing venous insufficiency. Hypoproteinemia was considered to be involved in CPE if plasma proteins were < 55 g/L and albumin < 25 g/L. Drug-induced CPE was considered if the patient received calcium channel blockers, non-steroidal anti-inflammatory drugs, corticosteroid or other drug known to induce leg edema. Lymphedema was considered when skin thickening was present. Finally, results of both investigators were confronted and discrepancies were solved by discussion. For each patient, the list of etiologies retained after this process was considered as the “reference diagnosis”.
BNP determination
BNP plasma levels were determined by immunoassay (Biosite, Triage) within days after the investigators' visit, when blood was collected for routine medical care. Results were not available for the investigators at the time of their diagnosis.
Statistics
Comparison of qualitative variables used test khi-2 test. For quantitative variables,
comparisons used the Student t test if they were normally distributed or the Mann-Whitney U test otherwise. Differences were considered significant if p< 0.05. For each type of CPE etiologies, agreement between clinical diagnosis and reference diagnosis was studied by Kappa coefficient (κ). Agreement was considered as good if κ > 0.80, moderate if κ was comprised between 0.60 and 0.80, or poor if κ < 0.60. We used a Receiver Operating Characteristic (ROC) curve to compare the different sensitivities and specificities according to the values of BNP for the reference diagnosis of chronic heart failure. We used the Youden index to select the BNP threshold. Additionally, we calculated the Net Reclassification Improvement (NRI) of the best BNP threshold value for the diagnosis of CHF (16). The respective values of BNP and other variables recorded for the diagnosis of
chronic heart failure were studied as follows. First, by univariate analysis, we compared the variables of patients having chronic heart failure according to reference diagnosis to those without CHF. We run univariate and multivariable logistic regression analysis using chronic heart failure (yes/no) as the dependent variable, and BNP (below/above threshold) and all the variables with p<0.10 in the univariate analysis as independent variables, and excluding variables related to chest radiography because of missing data. Concerning sample size, we did not estimate a required sample size, simply intended to include as many patients as possible. A post-hoc calculation shows that our study had 93% power to detect BNP sensitivity and specificity greater than 0.80, given the observed prevalence of heart failure. All calculations were made using STATA software (v 13, StataCorp LP, USA)
Results
Patients and chronic peripheral edema etiologies
Hundred and forty-one patients (28 males and 113 females, aged 86 +/- 6 years) were included in the study and their characteristics are showed in Table 1. Echocardiography was available in 119 patients (84.4%). The distribution of CPE etiologies and their type are listed in the Table 2. Multiple CPE etiologies were found in 84 patients (60%) and single etiology in 53 (38%). The number of CPE etiologies identified by investigators were significantly greater that those identified by clinicians (260 versus 185, p<0.0001).
Discrepancies between investigators diagnosis occurred in 9 patients, mostly related to missing extraction of data from the medical records, leading to an easy resolvation. As compared to the reference diagnosis, clinical diagnosis recorded a greater percentage of patients with undetermined etiology or with a single CPE etiology (p<0.0001). Conversely, the percentage of patients with multiple CPE etiologies was significantly less. Agreement between clinical diagnosis and reference diagnosis was poor for most etiologies (κ < 0.60).
The role of hypoproteinemia and that of drugs were frequently and widely unrecognized.
They were mainly related to malnutrition and calcium channel blockers respectively.
Agreement between clinical and reference diagnosis for chronic heart failure is detailed in
Table 3. In 32 patients (23%), the clinical diagnosis for CHF was different from the
reference. Chronic heart failure was missed in 18 patients with chronic heart failure (13%) and was diagnosed in 14 (10%) without chronic heart failure.
BNP and other factors related to chronic heart failure
Characteristics of patients with chronic heart failure were compared to those of patients without chronic heart failure (Table 4). Patients with chronic heart failure had more frequently hypertension, history of acute heart failure, bilateral crackles, jugular
distension or hepatojugular reflux, ECG and chest radiography abnormalities. In addition, systolic blood pressure and plasma BNP values in this group were significantly greater than in patients without CHF, whereas plasma creatinine values were significantly less (Table 4).
We examined how were related BNP values to the reference diagnosis of chronic heart failure by a receiver operating characteristic (ROC) curve plotting 1-specificity against sensitivity for each value of BNP. The area under the ROC curve is 0.883. A BNP value of 274 pg/mL was selected from the maximal value of the Youden index. 0.89 specificity and 0.82 sensitivity This threshold BNP value had, for the diagnosis of heart failure in these patients, an Event NRI of 11.5% (i.e. proportion of patients without an initial clinical diagnosis of CHF in whom BNP correctly diagnosed CHF), a Non-event NRI of 6.3% (i.e.
patients with an initial clinical diagnosis of CHF in whom BNP accurately eliminated CHF), and an overall NRI of 0.18 (p = 0.037) (Supplementary data, Table S1).
Then we created a new discrete variable named high BNP: above/below this threshold (274 pg/mL). To examine respective associations of all the variables related to the reference diagnosis of CHF, we ran a first logistic regression model using chronic heart failure (yes/
no) as dependent variable, and the following variables as independent variables: high BNP, age, hypertension, history of acute heart failure, systolic blood pressure, crackles, jugular distension, hepatojugular reflux, ECG repolarization abnormalities, atrial fibrillation, ECG signs of prior myocardial infarction, plasma creatinine. The variables independently and significantly related to chronic heart failure were High BNP, systolic blood pressure,
pulmonary cracles and hepatojugular reflux (Table 5). High BNP was a major and significant contributor to explain variance in the model.
Comments
This study showed that BNP dosage is relevant to improve the etiological diagnosis of CPE in very old patients, in particular to identify CPE related to chronic heart failure. In addition, it showed that most of these patients had 2 or more etiologies of CPE and that their correct identification is far to be perfect in the clinical field. Recognition of chronic heart failure is a major step to implement appropriate treatments and to improve the prognosis of patients with CPE of cardiac origin.
The clinical utility of BNP dosage has been extensively studied in patients with acute dyspnea, and especially in the context of emergencies (11, 12, 13). A large consensus established that values below 100 pg/mL rule out the diagnosis of heart failure, and that values above 400 pg/mL is a strong argument for this diagnosis (17). However, studies investigating the relevance of BNP in the context of primary care for non-acute patients are less numerous and generally have found a much lower specificity for the diagnosis of heart failure. In these studies, patients were much younger than those in our study and most of the patients had dyspnea (18, 19, 20, 21, 22, 23, 24). To our knowledge our study is the first conducted among very old patients with CPE and without dyspnea. This clinical picture is known to be a quite common presentation of chronic heart failure in very old persons, probably because impaired exercise tolerance is often masked due to lack of physical activity or low reporting due to cognitive troubles (14, 25). Heart failure is known to be often misdiagnosed in such population. A recent study in the UK shown cardiologists systematically assessed elder institutionalized persons and detected heart failure in 22% of them (25). The diagnosis was ignored in 9 of 10 patients and conversely, in 3 of 4 patients with previously diagnosed heart failure, the diagnosis was not confirmed. In our study, we also found that heart failure was widely misdiagnosed. In addition, numerous causes of CPE
can be associated in the same old patient, which make their identification more complex, including that of chronic heart failure.
In our study, diagnostic performance of BNP was excellent using 274 pg/mL value as the cut-off point. This is value is quite close to the classic cut-off points of 100 and 400 pg/mL.
It is also consistent with BNP cut-off values found by others for non-acute heart failure diagnosis (16, 26, 27). In fact, aging process is associated with an age-associated increase in secretion of heart natriuretic peptides (28, 29), and also with a decrease in their renal elimination, but the effect is more pronounced on NT-proBNP than on BNP (16).
In our study, we observed that not only heart failure, but also other conditions responsible for CPE were improperly identified in the clinical field. In particular, the role of drugs and hypoproteinemia/malnutrition were widely underestimated. Also these conditions are modifiable by changes in drug regimen, nutritional support and physical activity.
As limitations, our study was single-center and included a limited number of patients, so it is not is not sure that our sample were representative of the general population of elderly patients presenting with CPE. Also, 16% of the included patients had not a recent
echocardiography, so the reference diagnosis of heart failure in these patients was based in clinical criteria and that could have lead to some incorrect reference diagnosis of heart failure. However, the combined sensitivity and specificity of the Framingham clinical criteria, which we employed in those patients, is good (sensitivity 92%, specificity 79%) and were applied only to a minority of patients. Finally, external validation in an independent study would be needed to confirm these results.
Overall, our study suggests that very old persons with CPE should be systematically assessed by a careful clinical approach, ECG, chest radiography and a single dosage of plasma BNP. By these simple means, it is possible to identify many conditions, including chronic heart failure, which might be improved by appropriate treatments.
Acknowledgments: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Statement of Conflict of Interest: The authors have no conflict of interest.
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Legend of Figure
ROC curve of plasma BNP for the diagnosis of chronic heart failure among very old patients with chronic peripheral edema. Arrow shows the threshold of 274 pg/mL having 0.89 specificity (Spe), 0.82 sensitivity (Se), 0.85 positive predictive value (PPV) and 0.86 negative predictive value (NPV). The corresponding values for classic BNP cut-off values (100 and 400 pg/mL) have been calculated.
Table 1: Characteristics of the patients. Results are expressed as mean +/- SD or numbers and percentage in brackets, except creatinine, creatinine clairance and BNP which are expressed as median and interquartile range in brackets.
Variable Total
(n=141) Demography and history
Age (years) 86.5 +/- 6.0
Males 28 (20)
Hypertension 96 (68)
Diabetes 31 (22)
Acute heart failure 33 (23)
Venous ulcer 24 (17)
Venous thromboembolism 23 (16)
Physical examination
Systolic BP (mmHg) 129 +/- 19
Diastolic BP (mmHg) 72 +/- 12
Bilateral pulmonary crackles 33 (23)
Jugular distension 22 (16)
Hepatojugular reflux 48 (34)
Bilateral edema 128 (91)
Local leg inflammation 17 (12)
Varicose veins 53 (38)
Skin hemosiderin 49 (35)
Electrocardiogram
Repolarization abnormalities 54 (38)
Atrial fibrillation 45 (32)
Prior myocardial infarction 17 (12)
Chest radiography*
Cardiothoracic index > 0.50* 92 (77)**
Pleural effusion* 18 (16)**
Alveolar or interstitial edema* 29 (26)**
Echocardiography (n = 119) †
Mean left ventricular ejection fraction (±
SD) † 56 (±12) †
* Chest radiography was missing in 6 patients with CHF and 15 patients without CHF
** Values are median and interquartile range
† Echocardiography was not performed in 22 patients (5 with CHF, 17 without) Ejection fraction < 50% † 33 (28) †
Biological values
Haemoglobin (g/dL) 11.8 +/- 1.5
Albumin (g/L) 31.1 +/- 5.4
Creatinine** (µg/mL) 76 (63-91)
Creatinine clairance** (mL/mn) 43 (33-61)
BNP** (pg/mL) 210 (106-463)
Cardiovascular treatments
Diuretics 48 (34)
Renine-angiotensine system inhibitors 49 (35)
Beta blockers 29 (21)
Anticoagulants 24 (17)
Antiplatelets 48 (34)
Table 2: Distribution and types of chronic peripheral edema etiologies diagnosed by clinicians and investigators (reference). Results are expressed as numbers and percentage in brackets. Agreement between clinical and reference diagnosis for each type of etiology was assessed by kappa coefficient.
Clinical diagnosis (n=141)
Reference diagnosis (n=141)
Comparison
Distribution of etiologies Patients with:
single etiology 75 (53) 53 (38)
P<0.0001
2 etiologies 43 (30) 56 (40)
3 etiologies or more 8 (6) 28 (20)
undetermined etiology 15 (11) 2 (1)
Total number of etiologies 185 260 P<0.0001
Types of etiologies
Venous disease 83 (59) 97 (69) Κ = 0.42
Heart failure 57 (40) 61 (43) Κ = 0.53
Hypoproteinemia 26 (18) 53 (38) Κ = 0.44
Drug-induced edema 10 (7) 36 (26) Κ = 0.36
Lymphoedema 6 (4) 9 (6) Κ = 0.65
Other 3 (2) 4 (3) -
Table 3: Agreement between the diagnoses of chronic heart failure (CHF) done by clinicians and that done by investigators (reference). Kappa coefficient was 0.53, indicating a poor agreement.
Clinical diagnosis Reference diagnosis
Pts with CHF (n=57)
Pts without CHF (n=84)
Pts with CHF (n=61) 43 18
Pts without CHF (n=80)
14 66
Table 4: Characteristics of patients having chronic heart failure compared with those of patients without chronic heart failure (CHF). Results are expressed as mean +/- SD or numbers and percentage in brackets, except creatinine, creatinine clearance and BNP which are expressed as median and interquartile range in brackets.
Variable With CHF
(n=61)
Without CHF (n=80)
P
Demography and history
Age (years) 87.4 +/- 6.2 85.7 +/- 5.7 0.09
Males 14 (23) 14 (18) 0.55
Hypertension 48 (79) 48 (60) 0.03
Diabetes 17 (28) 14 (17) 0.20
Acute heart failure 23 (38) 10 (12) 0.0008
Venous ulcer 12 (20) 12 (15) 0.61
Venous thromboembolism 9 (15) 14 (17) 0.83
Physical examination
Systolic BP (mmHg) 133 +/- 21 127 +/- 18 0.04
Diastolic BP (mmHg) 73 +/- 14 71 +/- 10 0.26
Bilateral pulmonary crackles 25 (41) 8 (10) 0.0001
Jugular distension 19 (31) 3 (4) <0.0001
Hepatojugular reflux 37 (61) 11 (14) <0.0001
Bilateral edema 58 (95) 70 (87) 0.21
Local leg inflammation 6 (10) 11 (14) 0.65
Varicose veins 18 (30) 35 (44) 0.12
Skin hemosiderin 23 (37) 26 (352) 0.64
Electrocardiogram
Repolarization abnormalities 31 (51) 23 (29) 0.012
Atrial fibrillation 34 (56) 11 (14) <0.0001
Prior myocardial infarction 13 (21) 4 (5) 0.003 Chest radiography*
Cardiothoracic index > 0.50* 51 (93)* 41 (63)* 0.0003
Pleural effusion* 15 (28)* 3 (5)* 0.002
Alveolar or interstitial edema* 23 (43)* 6 (10)* 0.0001
* Chest radiography was missing in 6 patients with CHF and 15 patients without CHF
** Values are median and interquartile range Biological values
Haemoglobin (g/dL) 11.8 +/- 1.4 11.8 +/- 1.6 0.91
Albumin (g/L) 31.0 +/- 5.5 31.1 +/- 5.3 0.94
Creatinine** (µg/mL) 80 (67-104) 74 (60-88) 0.03 Creatinine clairance** (mL/
mn)
42 (32-57) 44 (35-65) 0.49
BNP** (pg/mL) 490 (324-954) 137 (79-203) <0.0001
Table 5: Bivariate and multivariable logistic regression analysis for associations with the reference diagnosis of chronic heart failure in the 141 participants.
OR : odds-ratio ; 95%CI : 95% confidence interval
Variables Bivariate Multivariable
OR 95%CI P OR 95%CI P
Demography and history
Age (yrs) 1.05 (0.99-1.11) 0.09
Hypertension 2.46 (1.15-5.26) 0.03
Acute heart failure 4.23 (1.83-9.82) 0.0008 Physical examination
Systolic blood pressure (mmHg)
1.02 (1.00-1.04) 0.04 1.03 (1.01-1.07) 0.008
Bilateral pulmonary crackles
6.25 (2.56-15.24 )
0.0001 8.78 (1.80-42.75 )
0.004
Hepatojugular reflux 11.6 1
(3.25-41.53 )
<0.000 1
4.26 (1.05-17.22 )
0.04
Jugular distension 9.67 (4.27-21.91 )
<0.000 1 Electrocardiogram
Repolarization
abnormalities 2.56 (1.27-5.14) 0.012
Atrial fibrillation 7.90 (3.51-17.8) <0.000 1 Prior myocardial infarction 5.15 (1.59-16.7) 0.003 Biological values
Creatinine (µg/mL) 1.01 (0.99-1.02) 0.03
High BNP 35.8
6
(13.84-92.9 4)
<0.000 1
32.6 8
(8.05-132.6 8)
<0.000 1
sensitivity
0,0 0,3 0,5 0,8 1,0
1 - specificity
0,0 0,3 0,5 0,8 1,0
Supplementary Data
The value of BNP plasma levels in very old persons with chronic peripheral edema Belmin J et al.
Table S1. Net reclassification improvement of plasma BNP for the diagnosis of CHF in older patients with peripheral edema.
BNP = Brain natriuretic peptide; CHF = chronic heart failure; NRI = net reclassification improvement; SD = standard deviation.
a) Initial diagnostic of CHF incorrectly reclassified by BNP as not having CHF (i.e. “moving down” with event).
b) Initial diagnostic of CHF adequately reclassified by BNP as not having CHF (i.e. “moving down” with no event).
c) Initial diagnostic of not having CHF adequately reclassified by BNP as CHF (i.e. “moving up” with event).
d) Initial diagnostic of not having CHF incorrectly reclassified by BNP as CHF (i.e. “moving up” with no event).
Event NRI corresponds to the net percentage of patients with the event of interest (heart failure) correctly
reclassified upward with respect to the initial category of risk (here, clinical initial diagnostic). It equals the improvement in sensitivity. Non-event NRI is the net percentage of persons without the event of interest (heart failure) correctly reclassified downward and equals the improvement in specificity. Overall NRI is the sum of Event and Non-event NRIs. However, overall NRI is implicitly weighted for the event rate and cannot be interpreted as a percentage (16).
Patients with heart failure (n = 61) Plasma BNP > 274 pg/ml
Patients without heart failure (n = 80) Yes No Total
Clinical initial diagnostic of heart failure
Yes 38 5 (a)
3 11 (b) 57
No 12 (c) 6
6 (d) 60 84
Total 59 82
Estimates Event NRI Non-event NRI Overall NRI (± SD) p
0.1147 0.0625 0.1772 ± 0.085 0.037
