Comparison of midregional pro-atrial natriuretic peptide with N-terminal pro-B-type natriuretic â¨...

doi: 10.1111/j.1365-2796.2009.02135.x

Comparison of midregional pro-atrial natriureticpeptide with N-terminal pro-B-type natriureticpeptide in the diagnosis of heart failure

M. Potocki1,5, T. Breidthardt1, T. Reichlin1, S. Hartwiger1, N. G. Morgenthaler2, A. Bergmann2, M. Noveanu1,H. Freidank3, A. B. Taegtmeyer1, K. Wetzel1, T. Boldanova1, C. Stelzig1, R. Bingisser1, M. Christ4 & C. Mueller1

From the 1Department of Internal Medicine, University Hospital, Basel, Switzerland; 2Research Department, B.R.A.H.M.S. AG,Hennigsdorf ⁄Berlin, Germany; 3Department of Laboratory Medicine, University Hospital, Basel, Switzerland; 4KlinikumNuernberg, Internal Medicine, Nuernberg; and 5Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany

Abstract. Potocki M, Breidthardt T, Reichlin T,

Hartwiger S, Morgenthaler NG, Bergmann A,

Noveanu M, Freidank H, Taegtmeyer AB, Wetzel K,

Boldanova T, Stelzig C, Bingisser R, Christ M,

Mueller C (University Hospital, Basel, Switzerland,

B.R.A.H.M.S. AG, Hennigsdorf ⁄Berlin, Germany;

Klinikum Nuernberg, Internal Medicine, Nuernberg;

and Herz-Zentrum Bad Krozingen, Bad Krozingen,

Germany). Comparison of midregional pro-atrial natri-

uretic peptide with N-terminal pro-B-type natriuretic

peptide in the diagnosis of heart failure. J Intern Med

2010; 267: 119–129.

Objectives. The concentration of atrial natriuretic pep-

tide (ANP) in the circulation is approximately 10- to

50- fold higher than B-type natriuretic peptide (BNP).

We sought to compare the accuracy of midregional

pro-atrial natriuretic peptide (MRproANP) measured

with a novel sandwich immunoassay with N-terminal

pro-B-type natriuretic peptide (NTproBNP) in the

diagnosis of heart failure.

Design. The diagnosis of heart failure was adjudicated

by two independent cardiologists using all available

clinical data (including BNP levels) in 287 consecutive

patients presenting with dyspnoea to the emergency

department (ED). MRproANP and NTproBNP levels

were determined at presentation in a blinded fashion.

Results. Heart failure was the adjudicated final diagno-

sis in 154 patients (54%). Median MRproANP was

significantly higher in patients with heart failure as

compared to patients with other causes of dyspnoea

(400 vs. 92 pmol L)1, P < 0.001). The diagnostic

accuracy of MRproANP was very high with an area

under the receiver operating characteristic curve of

0.92 and was comparable with that of NTproBNP

(0.92, P = 0.791). Moreover, MRproANP provided

incremental diagnostic information to BNP and

NTproBNP in patients presenting with BNP levels in

the grey zone between 100 and 500 pg mL)1.

Conclusion. Midregional pro-atrial natriuretic peptide is

as accurate in the diagnosis of heart failure as

NTproBNP. MRproANP seems to provide incremental

information on top of BNP or NT-proBNP in some

subgroups and should be further investigated in other

studies.

Keywords: dyspnoea, emergency diagnosis, heart fail-

ure, MRproANP, natriuretic peptides.

Introduction

Heart failure (HF) is common, associated with high

morbidity and mortality, and difficult to diagnose,

particularly, in the emergency department (ED) [1, 2].

Dyspnoea is the leading symptom of most HF

patients. Unfortunately, neither patient history nor

physical examination can accurately differentiate

ª 2009 Blackwell Publishing Ltd 119

Original Article |

dyspnoea because of HF from dyspnoea due to other

causes, such as pulmonary diseases [3, 4]. However,

accurate diagnosis is necessary for the selection of the

most appropriate treatment.

B-type natriuretic peptides are quantitative markers of

HF that have been shown to be very helpful in the

diagnosis of HF. The use of B-type natriuretic peptide

(BNP) and its amino-terminal fragment, N-terminal

pro-B-type natriuretic peptide (NTproBNP), signifi-

cantly increases the diagnostic accuracy in the ED [5,

6] and thereby improves patient evaluation and treat-

ment [7–9].

The concentration of atrial natriuretic peptide (ANP)

in the circulation is approximately 10- to 50- fold

higher than that of BNP [10]. Therefore, the biologi-

cal signal reflected by the increased ANP may be

pathophysiologically and therefore diagnostically even

more important than the signal of BNP. However,

analytical difficulties with previous ANP assays and

inferior clinical results as compared with BNP in

early pilot studies have hampered and distracted fur-

ther research on the diagnostic use of ANP and its

precursors [11]. Mature ANP is derived from the pre-

cursor N-terminal-proANP (NTproANP), which is sig-

nificantly more stable in the circulation than the

mature peptide and is therefore thought to be a more

reliable substrate for analysis [12]. Furthermore, since

NTproANP has been shown to be subject of further

fragmentation [13, 14], immunoassays for measure-

ment of a mid-regional sequence of proANP

(MRproANP) may have an advantage [15]. We there-

fore determined plasma levels of MRproANP in unse-

lected patients presenting to the ED with dyspnoea

and compared the accuracy of MRproANP in the

diagnosis of HF with that of NTproBNP.

Methods

Study population and design

We prospectively enrolled 287 consecutive patients pre-

senting to the ED of the University Hospital Basel with

dyspnoea as the most prominent symptom from April

2006 to March 2007. Patients under 18 years of age,

patients on haemodialysis and trauma patients were

excluded. The study was carried out according to the

principles of the Declaration of Helsinki and approved

by the local ethics committee. Written informed consent

was obtained from all participating patients.

Clinical evaluation of patients

Patients underwent an initial clinical assessment that

included clinical history, physical examination, ECG,

pulse oximetry, blood tests and chest X-ray. For each

patient enrolled in the study, ED physicians assessed

the probability that the patient had HF (by assigning a

value of 0% to 100% clinical certainty) as the cause

of dyspnoea using all available information from the

physical examination, ECG, chest X-ray and blood

tests including BNP. BNP values were available at

presentation in all enrolled patients.

Reference (‘Gold’) standard definition of heart failure

Two independent cardiologists reviewed all medical

records pertaining to the patient and classified the diag-

nosis as dyspnoea caused by HF or dyspnoea because

of causes other than HF. Both cardiologists had access

to all available medical records pertaining to the patient

from the time of ED presentation to the results of the

90-day follow up. This information included BNP lev-

els, chest X-ray, medical history not available at the

time of admission, echocardiography, left ventriculog-

raphy (performed at the time of cardiac catheterization),

pulmonary function test, CT scan, right heart catheteri-

zation, hospital course, response to therapy, autopsy

data for deceased patients and information about clini-

cal events or readmissions during the 90-day follow up

period. The BNP level was considered as a quantitative

marker of HF and therefore interpreted as a continuous

variable to make best use of the information provided

by this test. Absolute BNP values were adjusted for the

presence of both kidney disease and obesity to maxi-

mize diagnostic accuracy [16].

Measurement of natriuretic peptides

At presentation to the ED, blood samples for determi-

nation of MRproANP and NTproBNP levels were col-

M. Potocki et al. | MRproANP and NTproBNP in the diagnosis of heart failure

120 ª 2009 Blackwell Publishing Ltd Journal of Internal Medicine 267; 119–129

lected into tubes containing potassium EDTA. After

centrifugation, samples were immediately frozen at

)80 �C until later analysis. Detection of MRproANP

was performed using a sandwich immunoassay

(MRproANP LIA, B.R.A.H.M.S, Hennigsdorf ⁄Berlin,Germany) as described in detail elsewhere [15]. The

functional assay sensitivity (interassay coefficient of

variance <20%) is 20 pmol L)1. The stability of

MRproANP at room temperature is >24 h. After 7 days

at room temperature, the degradation of MRproANP

does not exceed 20%. This assay allows measurement

of MRproANP in serum and plasma (with EDTA, hepa-

rin, or citrate) [14]. Median MRproANP in 325 healthy

individuals in previous investigations was 45 pmol L)1

(95% confidence interval (CI) 43 to 49 pmol L)1) [15].

NTproBNP levels were determined by a quantitative

electrochemiluminescence immunoassay (Elecsys pro-

BNP; Roche Diagnostics AG, Zug, Switzerland). BNP

was measured by a microparticle enzyme immunoassay

(AxSym; Abbott Laboratories, Abbott Park, IL, USA).

End-points

The primary end-point was to compare the accuracy

of MRproANP with that of NTproBNP to diagnose

HF. As BNP levels were available for the reference

(‘Gold’) standard diagnosis of HF, the comparison of

the MRproANP with BNP was considered biased in

favour of BNP and, therefore, the comparisons were

made only between MRproANP and NTproBNP. The

secondary end-point was to investigate, whether

the addition of MRproANP to clinical judgement in the

ED, including chest X-ray and BNP information,

would further increase diagnostic accuracy.

Statistical analysis

Univariate data on demographic and clinical features

were compared by Mann–Whitney U test or Fisher’s

exact test as appropriate. Medians of each marker in

those with and without HF were compared using non-

parametric testing; otherwise, MRproANP and

NTproBNP were log-transformed to achieve a normal

distribution. Receivers operating characteristic (ROC)

curves were utilized to evaluate the utility of

MRproANP and NTproBNP for the diagnosis of HF

and areas under the curve (AUCs) were calculated for

both markers. AUCs were compared according to the

method by Hanley and McNeil [17]. The optimal cut-

off point was determined by selecting the point on the

ROC curve that maximized both sensitivity and speci-

ficity. The optimum cut-off point for ED clinical cer-

tainty of HF was chosen at ‡80%, a cut-off point

providing reasonable certainty and practical applicabil-

ity [18]. Logistic regression was used to combine clini-

cal judgement with MRproANP data in predicting final

diagnosis. The diagnostic accuracies of both assays at

optimal cut-off concentrations as determined by ROC

analysis were compared by the McNemar test (compari-

son of discordant pairs of false biochemical classifica-

tions). To determine odds ratios for the detection of HF

with respect to MRproANP and NTproBNP cut-off

points of highest diagnostic accuracy, logistic regres-

sion analysis was performed unadjusted and adjusted

for significant covariates in univariate analysis (age,

prior history of HF, prior myocardial infarction, esti-

mated glomerular filtration rate, haemoglobin, pulmo-

nary rales, peripheral oedema and jugular venous

distension). Spearman’s coefficient of rank correlation

was used to assess the relation of MRproANP and

NTproBNP concentrations in the study population.

Body mass index (BMI) was calculated using the con-

ventional formula of weight in kilograms divided by

the square of height in meters. Normal weight was

defined as a BMI <25 kg m)2, overweight as a BMI

between 25 kg m)2 and 29.9 kg m)2 and Obesity as a

BMI of 30 kg m)2 or greater, according to the defini-

tion of the World Health Organization. Glomerular fil-

tration rate was calculated using the Modification of

Diet in Renal Disease (MDRD) formula [19]. Data

were statistically analysed with SPSS 15.0 software

(SPSS Inc, Chicago, IL, USA) and the MedCalc 9.3.9.0

package (MedCalc Software, Mariakerke, Belgium).

All probabilities were two-tailed and P < 0.05 was con-

sidered to indicate statistical significance.

Results

Study population

A total of 287 patients were enrolled in this study

(Table 1). The median age was 77 years and there


ª 2009 Blackwell Publishing Ltd Journal of Internal Medicine 267; 119–129 121

Table 1 Patients characteristics

Characteristic All patients (n = 287)

Heart failure

(n = 154, 54%)

No heart failure

(n = 133, 46%) P-value

Age (years)b 77 (68–83) 80 (75–85) 71 (58–79) <0.001

Male gender (%) 52 51 53 0.906

Body mass index (kg m)2)a 26 ± 6 27 ± 6 26 ± 7 0.124

History (%)

Hypertension 68 78 56 <0.001

History of heart failure 24 40 7 <0.001

Coronary artery disease 28 38 16 <0.001

Diabetes mellitus 18 24 11 0.006

Chronic obstructive pulmonary disease 34 27 42 0.006

Chronic kidney disease 28 44 11 <0.001

Shortness of breath (%)

Whilst walking up a slight incline 20 9.7 32 <0.001

Whilst walking on level ground 40 45 35 0.109

At rest 40 46 33 0.034

Physical examination findings (%)

Heart rate (bpm)a 93 ± 23 93 ± 25 92 ± 19 0.495

Systolic blood pressure (mmHg)a 138 ± 26 135 ± 27 140 ± 25 0.098

Diastolic blood pressure (mmHg)a 83 ± 16 82 ± 17 83 ± 14 0.455

Respiratory rateb 24 (20–28) 24 (20–28) 24 (18–28) 0.678

Rales 54 64 43 0.001

Lower extremity oedema 42 57 26 <0.001

Hepatojugular reflux 8.0 12 3.8 0.016

Jugular venous distension 28 44 11 <0.001

Chronic Medication (%)

b-blockers 39 57 17 <0.001

Angiotensin-converting enzyme

inhibitor ⁄ angiotensin-receptor blockers49 62 34 <0.001

Loop diuretics 52 64 38 <0.001

Calcium antagonists 18 21 14 0.070

Digoxin 4.9 5.2 4.5 0.169

Spironolactone 2.4 3.9 0.8 0.041

Laboratory findings

Serum creatinine (lmol L)1)b 85 (66–120) 99 (79–147) 71 (56–96) <0.001

eGFR (mL min)1 1.73m)2)b 67 (44–89) 54 (36–73) 80 (63–112) <0.001

Blood urea nitrogen (mmol L)b 7.3 (5.4–12.0) 9.7 (6.7–15.6) 6.0 (4.4–7.7) <0.001

Sodium (mmol L)b 137 (134–139) 137 (135–139) 137 (134–140) 0.238

Haemoglobin (g L)b 133 (118–145) 129 (112–141) 138 (125–150) <0.001

Troponin T (lg L)b (n = 192) 0.01 (0.01–0.03) 0.01 (0.01–0.04) 0.01 (0.01–0.01) <0.001

BNP (pg mL)1)b 349 (90–1120) 976 (467–1925) 81 (39–181) <0.001

NT-proBNP (pg mL)1)b 1656 (314–6105) 5757 (1924–13 243) 300 (76–974) <0.001

MR-proANP (pmol L)1)b 221 (93–441) 400 (246–643) 92 (60–173) <0.001



were 149 men (52%). Arterial hypertension was

present in 68% of the patients, 28% had coronary

heart disease and 34% had chronic obstructive pul-

monary disease. On examination, 54% of patients

had pulmonary rales, 42% had lower extremity

oedema and 28% had jugular venous distension.

Diuretics (52%) were the most common prescribed

chronic medications, followed by ACE-inhibitors or

angiotensin-receptor-blockers (49%) and b-blockers(39%).

Final (gold standard) diagnosis

The adjudicated gold standard diagnosis was HF in

154 (54%) patients and no HF in 133 patients.

Patients without HF had chronic obstructive pulmo-

nary disease (57 patients), pneumonia (32 patients),

pulmonary embolism (8 patients), malignancy (7

patients), hyperventilation (5 patients) and other

causes of dyspnoea such as interstitial lung disease,

asthma or bronchitis (24 patients).

Natriuretic peptide levels and diagnosis of HF

The levels of MRproANP and NTproBNP in patients

with and without an adjudicated gold standard diagno-

sis of HF are shown in Fig. 1. The median

MRproANP concentration of patients with HF

(400 pmol L)1, IQR 246–642 pmol L)1) was signifi-

cantly higher than of those without HF (92 pmol L)1,

IQR 92–173 pmol L)1; P < 0.001 for difference). The

median NTproBNP concentration in patients with HF

was 5757 pg mL)1 (IQR 1924–13243 pg mL)1) vs.

300 pg mL)1 (IQR 76–974 pg mL)1) in patients

without HF (P < 0.001 for difference). Spearman’s

coefficient of rank correlation was 0.899 between

MRproANP and NTproBNP (P < 0.001).

The AUC of MRproANP was 0.92 (95% CI 0.88 to

0.95) for the diagnosis of HF, comparable to the AUC

of NTproBNP with 0.92 (95% CI 0.89 to 0.95;

P = 0.791; Fig. 2a). On the basis of the ROC analy-

sis, the optimal diagnostic cut-off value for

MRproANP and NTproBNP to reach the highest diag-

nostic accuracy was 206 pmol L)1 and 1540 pg mL)1

respectively. At this cut-off, diagnostic accuracy, sen-

sitivity and specificity for MRproANP were all 84%.

Logistic regression analysis confirmed MRproANP as

a powerful predictor of HF in both univariate and

multivariate analyses (Table 2).

The AUC for the combination of ED-probability with

MRproANP was significantly higher than for ED-

probability alone (P = 0.016, Fig. 2b). The diagnostic

accuracy for clinical judgement with high ED-probabil-

Table 1 Continued

Characteristic All patients (n = 287)

Heart failure

(n = 154, 54%)

No heart failure

(n = 133, 46%) P-value

Echocardiography findings (%) (n = 116) (n = 89) (n = 27)

Left ventricular ejection fractionb 56 (35–65) 50 (33–60) 65 (60–65) <0.001

eGRF, estimated glomerular filtration rate; MRproANP, midregional pro-atrial natriuretic peptide; NTproBNP, N-terminal pro-B-type natriureticpeptide.aMeans ± SD. bMedian (25th–75th percentile).

NT

-pro

BN

P c

once

ntra

tion

(pg/

mL)

35 000

30 000

25 000

20 000

15 000

10 000

5000

0

MR

-proAN

P concentration (pm

ol/L)

1500

1200

900

600

300

0

MR-proANP NT-proBNP

Acute HF No acute HF Acute HF No acute HF

Fig. 1 The MRproANP and NTproBNP levels in patientswith and without heart failure – NTproBNP and MRproANPlevels for patients with dyspnoea caused by acute heart failure(HF) (n = 154) and patients with dyspnoea attributable toother causes (n = 133); all P < 0.001. Boxes represent the25th and 75th percentile, whereas whiskers represent theminimum to the maximum concentration, excluding outliers,which are displayed as separate points.



ity of HF (80% to 100% clinical certainty) was 79.4%.

For a composite decision based on ED-probability of

80% to 100% or MRproANP >206 pmol L)1, or both,

the diagnostic accuracy was 87.8%. Therefore,

MRproANP levels >206 pmol L)1 added to clinical

judgement would have increased the diagnostic accu-

racy considerably to almost 88% (P < 0.001) and

increased the sensitivity from 62% to 91%. A similar

improvement was observed for the combination of clin-

ical judgement and NTproBNP, resulting in a diagnos-

tic accuracy of 86.4%. Looking at the patients who

were additionally identified as having HF by

MRproANP compared to the other patients with heart

failure, we identify differences in following clinical

characteristics: These patients more often had an under-

lying chronic obstructive pulmonary disease (38% vs.

22%, P = 0.044), had less clinical signs of congestion

like rales (51% vs. 70%, P = 0.028), showed a better

ejection fraction (60[50–65]% vs. 41[28–60]%,

P = 0.012) and were more often on medical therapy

with ACE-Inhibitors or angiotensin-receptor-blockers

(76% vs. 57%, P = 0.03). Table 3 gives detailed diag-

nostic information including the appropriate decision

statistics for the clinical and biochemical diagnosis

of HF.

Subgroup analysis

The additional value of MRproANP in several impor-

tant subgroups where BNP and NTproBNP levels are

difficult to interpret is shown in Table 4. We focused

on patients with BNP values between 100 and

500 pg mL)1, GFR values <60 mL min)1 and patient

with BMI >30 kg m)2. In each of these subgroups of

patients, MR-proANP was added to a logistic regres-

sion model with BNP or NTproBNP to predict HF. In

patients with BNP values between 100 and

500 pg mL)1, MRproANP added significant addi-

tional information to BNP and NTproBNP (OR 8.9,

P = 0.022; respectively OR 9.8, P = 0.042).

NTproBNP showed no additional information to BNP

(OR 1.6, P = 0.37). For patients with BMI

>30 kg m)2, MRproANP showed only a trend for an

incremental effect on top of BNP or NTproBNP

(P = 0.063 and P = 0.084 respectively).

The associations of MRproANP, NTproBNP and BMI

were examined in patients with and without heart

failure. Especially in patients with heart failure,

1 - specificity1.00.80.60.40.20.0

sen

siti

vity

1.0

0.8

0.6

0.4

0.2

0.0

P = 0.791

NT-proBNP (AUC = 0.92)MR-proANP (AUC = 0.92)

1 - specificity1.00.80.60.40.20.0

sen

siti

vity

1.0

0.8

0.6

0.4

0.2

0.0

P = 0.016

ED-Probability combined with MR-proANP (AUC = 0.96)

MR-proANP (AUC = 0.92)ED-Probability (AUC = 0.90)

(a)

(b)

Fig. 2 (a) Receiver operating characteristic curves forNTproBNP and MRproANP to diagnose heart failure inpatients with dyspnoea – Area under the curve (AUC).(b) Receiver operating characteristic curve for emergencydepartment (ED)-probability, MRproANP, and both to diag-nose heart failure in patients with dyspnoea – ED-probabilityalone compared to the combination of ED-probability withMRproANP (P = 0.016).



MRproANP and NTproBNP seemed to differ regard-

ing their association with BMI (Fig. 3). Mean

MRproANP levels were not different in overweight

(BMI ‡ 30, n = 47) and obese (25 £ BMI < 30,

n = 38) patients compared to individuals with normal

BMI (BMI < 25, n = 69) (P = 0.346 for both), where-

as NTproBNP levels were lower in overweight and

obese patients than in normal weight patients (P =

0.025 for both). There was no statistically significant

difference for MRproANP and NTproBNP levels

between the BMI groups in patients without HF

(P = 0.222 and P = 0.314 respectively).

Discussion

In our cohort of unselected patients presenting to the

ED with dyspnoea, we compared the accuracy of

MRproANP measured by a novel sandwich immunoas-

say with that of NTproBNP in the diagnosis of HF. We

report four major findings. First, MRproANP levels

Table 2 Logistic regression analysis for prediction of heart failure by MR-proANP and NT-proBNP

Analyte

Optimal cut-off

concentration

Odds ratio

(95% CI) P

Diagnostic

accuracy, % False-positive, n False-negative, n

Unadjusted model

MR-proANP (pmol L)1) 206 26 (14–50) <0.001 84 22 25

NT-proBNP (pg mL)1) 1540 30 (16–56) <0.001 85 21 23

Adjusted modela

MR-proANP (pmol L)1) 206 20 (9–45) <0.001 83 25 23

NT-proBNP (pg mL)1) 1540 19 (9–42) <0.001 83 24 23

MRproANP, midregional pro-atrial natriuretic peptide; NTproBNP, N-terminal pro-B-type natriuretic peptide.aAdjusted for age, history of heart failure, prior myocardial infarction, glomerular filtration rate, haemoglobin, pulmonary rales, peripheraloedema, jugular venous distension.

Table 3 Diagnostic informationfor the clinical and biochemicaldiagnosis of HF

Optimal cut-off

concentration Sensitivity Specificity PPV NPV

Diagnostic

accuracy, %

Clinical judgement ‡80%a 62 100 1 0.69 79

MR-proANP (pmol L)1) 206 84 84 0.86 0.82 84

NT-proBNP (pg mL)1) 1560 85 85 0.87 0.83 85

Combinedb 91 84 0.86 0.89 88

PPV, positive predictive value; NPV, negative predictive value.aED-Probability for HF ‡ 80%. bClinical judgement (including BNP) combined with MR-proANP.

Table 4 Clinical utility providedby MRproANP in different sub-groups

Subgroup Subgroup criteria

MRproANP adds

to BNP

MRproANP adds

to NTproBNP

OR per

log10 P-value

OR per

log10 P-value

Grey zone BNP (n = 91) ‡100 and <500 pg mL)1 8.9 0.022 9.8 0.042

Renal dysfunction (n = 117) eGFR<60 mL min)1 5.1 0.291 10.1 0.132

Obesity (n = 61) BMI ‡30 kg m)2 20.6 0.063 24.8 0.084

eGRF, estimated glomerular filtration rate; BMI, body mass index; MRproANP, midregional pro-atrialnatriuretic peptide; NTproBNP, N-terminal pro-B-type natriuretic peptide.



were significantly higher in patients with dyspnoea due

to HF as compared to patients with dyspnoea because

of other causes. Second, the diagnostic accuracy of

MRproANP was very high with an AUC of 0.92 and

comparable with NTproBNP. The AUC for

MRproANP in this study was very similar to the AUC

reported for BNP and NTproBNP in previous ED stud-

ies recruiting patients with dyspnoea [5–7, 18]. A

recent meta-analysis based on prospective ED studies

documented that BNP and NTproBNP had comparable

accuracy in the diagnosis of acute heart failure [20].

Taking together the observations from this meta-

analysis and our findings, it seems appropriate to

conclude that MRproANP, BNP and NTproBNP are

equally useful as an aid for the diagnosis of HF in

patients with dyspnoea. Third, the addition of

MRproANP levels to the clinical judgement in the ED

that included chest X-ray and BNP levels, significantly

improved diagnostic accuracy for HF. This observation

was also found for NTproBNP and the question rises

whether there exists an additional value to BNP or the

information obtained by BNP was overruled by the

clinician. Indeed, the diminished diagnostic accuracy of

the clinical judgement including BNP was 79.4%

instead of 84% for BNP alone at a cut-off value of

500pg mL)1. This clearly indicates that the clinician

overruled the information obtained by BNP and another

second biomarker either MRproANP or NTproBNP

could encourage the physician to reassess his diagnosis.

Fourth, MRproANP seems to provide incremental

diagnostic information in patients presenting with BNP

levels in the grey zone.

This study has particular strengths. First, we enrolled

unselected, elderly patients presenting with dyspnoea

and which are therefore representative for an ED

population presenting with dyspnoea and diagnostic

uncertainty [6, 21]. Second, this is the first large

observational cohort study assessing patients with

dyspnoea that included BNP levels in the clinical

judgement in the ED and the adjudicated gold

standard diagnosis. We consider this aspect to be of

major importance as BNP levels have previously

been shown to significantly improve diagnostic

accuracy in the ED [6]. Accordingly, our adjudi-

cated gold standard diagnosis can be considered

superior to the gold standard diagnosis in previous

studies.

The evaluation and management of patients present-

ing to the ED with dyspnoea is challenging [4, 22,

23]. The currently recommended approach to patients

with dyspnoea in the ED is based on the combina-

tion of clinical evaluation, ECG, chest X-ray and

natriuretic peptides [5, 6, 24]. Our findings validate

and extend the observations made in a recent pilot

study evaluating MRproANP for the diagnosis of HF

[25]. Gegenhuber et al. retrospectively compared

MRproANP levels with NTproBNP and BNP levels

in 251 patients presenting with dyspnoea and sug-

gested that the diagnostic information obtained by

MRproANP measurements was similar to that

obtained with either NTproBNP or BNP measure-

ments. Our study differs from theirs mainly in three

aspects: (i) we measured MRproANP and NTproBNP

at the same time-point, whereas MRproANP was

measured 1 year after the initial measurement of

BNP and NTproBNP in their study; (ii) our results

were obtained in a cohort that can be considered rep-

resentative for ED patients with dyspnoea, whilst

their results were obtained in a nearly exclusive

(>90%) male patient population; (iii) the accuracy

of our adjudicated gold standard diagnosis can be

Fig. 3 Mean NTproBNP (black bars) and MRproANP(grey bars) levels in patients with heart failure, grouped bybody mass index (BMI).



considered to be even higher as BNP levels were

available.

The particular advantage of this study is the availabil-

ity of an assessment of clinical judgement by the ED

physician that included ECG, chest X-ray and BNP

levels. The combination of MRproANP with the clini-

cal judgement in the ED increased the accuracy for a

correct diagnosis of HF to almost 88% and increased

the sensitivity from 62% to 91%, which resulted in

fewer misdiagnosed false negative patients with HF

from 56 patients to only 14 patients. The addition of

MRproANP to the clinical evaluation would have

detected one-third more patients with HF. This

improvement would lead to a more rapid and more

accurate therapy that would most likely be associated

with a reduction in morbidity, mortality and treatment

cost. This observation is supported by recent studies

showing the cost-effectiveness of natriuretic peptides

leading to the correct diagnosis and therefore a

reduced rate of hospital admission, rate of admission

to intensive care and time to discharge [26, 27]. Given

the enormous public health burden of HF [22, 23], this

achievement seems to be of paramount importance.

Previous studies described the grey zones of BNP and

NTproBNP and the difficulties to diagnose or exclude

heart failure in this population [28, 29]. MRproANP

seemed to provide incremental diagnostic information

to BNP and NTproBNP in this patient population and

may therefore help to mitigate one of the major limi-

tations associated with the clinical use of BNP and

NTproBNP. Nevertheless, MRproANP is not seen as

a substitute for further echocardiographic evaluation

in this patient population. Also, several recent studies

have documented lower BNP and NTproBNP levels

in obese compared with non-obese patients [30–32].

Therefore, lower natriuretic peptide cut-points are

needed in the diagnosis of HF in obese patients. In

this study, MRproANP levels were not different

between HF patients according to BMI, a potential

additional advantage.

Another important factor is the stability of

MRproANP, which exceeds 24 h at room temperature.

This could be of great value for general practitioners

or other physicians in private practice who need to

send blood samples to an external laboratory.

Several limitations apply to this study. First, all stud-

ies attempting to use a clinical diagnosis as gold stan-

dards for a syndrome have some limitations.

Although the cardiologists were able to review all

medical records and follow-up information, misclassi-

fication remains a possibility because HF is a clinical

diagnosis and no ideal gold standard exists. Echocar-

diography was not available in all patients. Echocar-

diographic imaging may be difficult to perform in

patients with dyspnoea or with coexisting condition

such as obesity or lung disease. Echocardiography

may also not be sensitive enough to delineate cardiac

causes of acute dyspnoea for example when severe

hypertension leads to pulmonary oedema. However,

the availability of BNP levels on top of routine clini-

cal care has consistently been shown to improve the

diagnostic accuracy in patients presenting with dysp-

noea to the ED [5, 6], but on the other hand, the

availability of BNP for the Gold standard diagnosis

and the correlation between BNP, NTproBNP and

MRproANP is a potential source of bias. Second, the

high prevalence of HF in our study population could

favour the diagnostic performance of the biomarkers.

Therefore, the results cannot be generalized to other

patient populations (e.g. primary care patients). Third,

the number of patients in the grey zone for BNP or

NTproBNP was too small to draw definite conclu-

sions regarding the additive value of MRproANP in

these patients. Additional studies including the inter-

national, multi-centre Biomarkers in ACute Heart

Failure (BACH) study will need to quantify the num-

ber of patients reclassified with the dual marker

approach.

In conclusion, the findings from this large study of

consecutive patients with dyspnoea indicate that

MRproANP is a highly accurate test for the diagnosis

of HF. The accuracy of MRproANP is comparable

with that of BNP and NTproBNP. Particularly in areas

of uncertainty with BNP and NTproBNP (grey zone),

MRproANP seems to be of additive diagnostic

value and should be further investigated in future

studies.



Conflict of interest statement

The study was supported by research grants from the

Swiss National Science Foundation (PP00B-102853),

Brahms, the Department of Internal Medicine, Univer-

sity Hospital Basel, the Brandenburg Ministry of Eco-

nomics, Germany and the European Regional

Development Fund (EFRE ⁄ERDF). Dr Mueller has

received research support from Abbott, Biosite,

Brahms, Roche and Siemens as well as speaker’s hon-

oraria from Abbott, Bayer, Biosite, Brahms, Roche

and Dade Behring. Dr Morgenthaler is employer at

B.R.A.H.M.S. AG, a biotech company that developed

the midregional pro-atrial natriuretic peptide

(MRproANP) assay. Dr Bergmann is a member of the

board of directors and shareholder of B.R.A.H.M.S.

AG. Dr Bergmann and Dr Morgenthaler are inventors

of patents related to MRproANP.

References

1 Cleland JG, Swedberg K, Follath F et al. The EuroHeart Failure

survey programme – a survey on the quality of care among

patients with heart failure in Europe. Part 1: patient characteris-

tics and diagnosis. Eur Heart J 2003; 24: 442–63.

2 Mosterd A, Hoes AW. Clinical epidemiology of heart failure.

Heart 2007; 93: 1137–46.

3 Mueller C, Frana B, Rodriguez D, Laule-Kilian K, Perruchoud

AP. Emergency diagnosis of congestive heart failure: impact of

signs and symptoms. Can J Cardiol 2005; 21: 921–4.4 Wang CS, FitzGerald JM, Schulzer M, Mak E, Ayas NT. Does

this dyspneic patient in the emergency department have conges-

tive heart failure? JAMA 2005; 294: 1944–56.

5 Januzzi JL Jr, Camargo CA, Anwaruddin S et al. The N-termi-

nal Pro-BNP investigation of dyspnea in the emergency depart-

ment (PRIDE) study. Am J Cardiol 2005; 95: 948–54.6 Maisel AS, Krishnaswamy P, Nowak RM et al. Rapid measure-

ment of B-type natriuretic peptide in the emergency diagnosis

of heart failure. N Engl J Med 2002; 347: 161–7.7 Moe GW, Howlett J, Januzzi JL, Zowall H. N-terminal pro-

B-type natriuretic peptide testing improves the management of

patients with suspected acute heart failure: primary results of

the Canadian prospective randomized multicenter IMPROVE-

CHF study. Circulation 2007; 115: 3103–10.

8 Mueller C, Scholer A, Laule-Kilian K et al. Use of B-type

natriuretic peptide in the evaluation and management of acute

dyspnea. N Engl J Med 2004; 350: 647–54.9 Mueller C, Laule-Kilian K, Frana B et al. The use of B-type

natriuretic peptide in the management of elderly patients with

acute dyspnoea. J Intern Med 2005; 258: 77–85.

10 Mukoyama M, Nakao K, Hosoda K et al. Brain natriuretic pep-

tide as a novel cardiac hormone in humans. Evidence for an

exquisite dual natriuretic peptide system, atrial natriuretic

peptide and brain natriuretic peptide. J Clin Invest 1991; 87:

1402–12.

11 Cowie MR, Struthers AD, Wood DA et al. Value of natriuretic

peptides in assessment of patients with possible new heart fail-

ure in primary care. Lancet 1997; 350: 1349–53.

12 Vesely DL. Atrial natriuretic peptide prohormone gene expres-

sion: hormones and diseases that upregulate its expression.

IUBMB Life 2002; 53: 153–9.13 Cappellin E, Gatti R, Spinella P et al. Plasma atrial natriuretic

peptide (ANP) fragments proANP (1–30) and proANP (31–67)

measurements in chronic heart failure: a useful index for heart

transplantation? Clin Chim Acta 2001; 310: 49–52.14 Ala-Kopsala M, Magga J, Peuhkurinen K et al. Molecular het-

erogeneity has a major impact on the measurement of circulat-

ing N-terminal fragments of A- and B-type natriuretic peptides.

Clin Chem 2004; 50: 1576–88.15 Morgenthaler NG, Struck J, Thomas B, Bergmann A. Immuno-

luminometric assay for the midregion of pro-atrial natriuretic

peptide in human plasma. Clin Chem 2004; 50: 234–6.

16 Mueller C, Breidthardt T, Laule-Kilian K, Christ M, Perruchoud

AP. The integration of BNP and NT-proBNP into clinical medi-

cine. Swiss Med Wkly 2007; 137: 4–12.

17 Hanley JA, McNeil BJ. A method of comparing the areas under

receiver operating characteristic curves derived from the same

cases. Radiology 1983; 148: 839–43.18 McCullough PA, Nowak RM, McCord J et al. B-type natriuretic

peptide and clinical judgment in emergency diagnosis of heart

failure: analysis from Breathing Not Properly (BNP) Multina-

tional Study. Circulation 2002; 106: 416–22.19 Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney

function – measured and estimated glomerular filtration rate.

N Engl J Med 2006; 354: 2473–83.

20 Clerico A, Fontana M, Zyw L, Passino C, Emdin M. Compari-

son of the diagnostic accuracy of brain natriuretic peptide

(BNP) and the N-terminal part of the propeptide of BNP immu-

noassays in chronic and acute heart failure: a systematic review.

Clin Chem 2007; 53: 813–22.21 Lainchbury JG, Campbell E, Frampton CM, Yandle TG, Nicho-

lls MG, Richards AM. Brain natriuretic peptide and n-terminal

brain natriuretic peptide in the diagnosis of heart failure in

patients with acute shortness of breath. J Am Coll Cardiol

2003; 42: 728–35.

22 Hunt SA, Abraham WT, Chin MH et al. ACC ⁄AHA 2005

Guideline Update for the Diagnosis and Management of

Chronic Heart Failure in the Adult: a report of the American

College of Cardiology ⁄American Heart Association Task Force

on Practice Guidelines (Writing Committee to Update the 2001

Guidelines for the Evaluation and Management of Heart Fail-

ure): developed in collaboration with the American College of

Chest Physicians and the International Society for Heart and

Lung Transplantation: endorsed by the Heart Rhythm Society.

Circulation 2005; 112: e154–235.

23 Dickstein K, Cohen-Solal A, Filippatos G et al. ESC Guidelines

for the diagnosis and treatment of acute and chronic heart fail-

ure 2008: the Task Force for the Diagnosis and Treatment of



Acute and Chronic Heart Failure 2008 of the European Society

of Cardiology. Developed in collaboration with the Heart Fail-

ure Association of the ESC (HFA) and endorsed by the Euro-

pean Society of Intensive Care Medicine (ESICM). Eur Heart J

2008; 29: 2388–442.24 Collins SP, Ronan-Bentle S, Storrow AB. Diagnostic and prog-

nostic usefulness of natriuretic peptides in emergency depart-

ment patients with dyspnea. Ann Emerg Med 2003; 41: 532–45.

25 Gegenhuber A, Struck J, Poelz W et al. Midregional pro-A-type

natriuretic peptide measurements for diagnosis of acute destabi-

lized heart failure in short-of-breath patients: comparison with

B-type natriuretic peptide (BNP) and amino-terminal proBNP.

Clin Chem 2006; 52: 827–31.26 Mueller C, Laule-Kilian K, Schindler C et al. Cost-effectiveness

of B-type natriuretic peptide testing in patients with acute dysp-

nea. Arch Intern Med 2006; 166: 1081–7.

27 Siebert U, Januzzi JL Jr, Beinfeld MT, Cameron R, Gazelle GS.

Cost-effectiveness of using N-terminal pro-brain natriuretic

peptide to guide the diagnostic assessment and management of

dyspneic patients in the emergency department. Am J Cardiol

2006; 98: 800–5.

28 van Kimmenade RR, Pinto YM, Januzzi JL Jr. Importance and

interpretation of intermediate (gray zone) amino-terminal pro-

B-type natriuretic peptide concentrations. Am J Cardiol 2008;

101: 39–42.

29 Brenden CK, Hollander JE, Guss D et al. Gray zone BNP lev-

els in heart failure patients in the emergency department: results

from the Rapid Emergency Department Heart Failure Outpatient

Trial (REDHOT) multicenter study. Am Heart J 2006; 151:

1006–11.

30 Krauser DG, Lloyd-Jones DM, Chae CU et al. Effect of body

mass index on natriuretic peptide levels in patients with acute

congestive heart failure: a ProBNP Investigation of Dyspnea in

the Emergency Department (PRIDE) substudy. Am Heart J

2005; 149: 744–50.

31 Mehra MR, Uber PA, Park MH et al. Obesity and suppressed

B-type natriuretic peptide levels in heart failure. J Am Coll Car-

diol 2004; 43: 1590–5.32 Wang TJ, Larson MG, Levy D et al. Impact of obesity on plasma

natriuretic peptide levels. Circulation 2004; 109: 594–600.

Correspondence: Dr med. Mihael Potocki, Department of Internal

Medicine, University Hospital Basel, Petersgraben 4, 4031 Basel,

Switzerland.

(fax: ++41 ⁄ 612655353; e-mail: [email protected]).



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