Skip Navigation

European Journal of Heart Failure 2005 7(4):552-556; doi:10.1016/j.ejheart.2004.12.001
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Hülsmann, M.
Right arrow Articles by Pacher, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hülsmann, M.
Right arrow Articles by Pacher, R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2005 European Society of Cardiology

Incidence of normal values of natriuretic peptides in patients with chronic heart failure and impact on survival: A direct comparison of N-terminal atrial natriuretic peptide, N-terminal brain natriuretic peptide and brain natriuretic peptide

Martin Hülsmanna,*, Rudolf Bergera, Deddo Mörtla, Odette Goreb, Brigitte Meyera and Richard Pachera

a Department of Cardiology, University of Vienna Waehringer Guertel 18-20, A-1090 Vienna, Austria
b LBI of Cardiovascular Research Vienna, Austria

* Corresponding author. Tel.: +43 1 404004616; Fax: +43 1 4081148. E-mail address: martin.huelsmann{at}meduniwien.ac.at


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Aims: N-ANP, N-BNP and BNP are proven to be excellent markers for diagnosis and the prediction of outcome in heart failure patients. Published studies on this subject differ in respect of their design and are therefore difficult to compare. The EuroHeart Failure Survey was undertaken to evaluate the drug prescription rate; the cohort of this survey best reflects clinical practice. The purpose of the present study was to compare the three hormones in clinical practice for the purpose of diagnosis and the prediction of outcome. Attention was focused on patients with normal values and the implications of these on survival.

Methods and results: Of 341 patients recruited in the Austrian centers of the survey, blood samples for the determination of N-ANP, N-BNP and BNP were taken from 112 patients. Mortality within the observation period was defined as the endpoint. Normal levels of the hormones were found in 5% of cases for N-ANP, 25% for N-BNP and 30% for BNP. The mortality of patients with normal values was low (0%, 3% and 6%, respectively) and occurred late (after more than 23 months). Above-median levels of all three hormones resulted in a comparable mortality (51% survival for N-ANP, 50% for BNP and 49% for N-BNP).

Conclusions: In a clinical setting, the risk stratification for outcome is similar for N-ANP, N-BNP and BNP. More importantly, all hormones are reliable parameters to diagnose CHF using normal values as a cut-point. However, N-ANP appears to be more sensitve than BNP or N-BNP.

Key Words: Chronic heart failure • Natriuretic peptides • N-ANP • N-BNP • BNP • Prognosis

Received September 15, 2004; Revised December 1, 2004; Accepted December 1, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Natriuretic peptides have repeatedly been shown to be excellent markers for diagnosis and risk stratification in heart failure [1–10]. Information about the comparability of BNP, N-BNP and N-ANP in respect of outcome in a clinical cohort is limited. Although healthy volunteers have been shown to have normal values of natriuretic peptides [11], recently published data [12] has shown that 21% of symptomatic heart failure cases have false negative levels of BNP. These findings stimulated a critical editorial by Packer, about the value of natriuretic peptides as a diagnostic tool [12a]. Lainchbury [8] compared N-BNP and BNP for diagnosis in a cohort presenting with dyspnea and found remarkable differences in the sensitivity of different test kits. This implies that natriuretic peptides are not equipotent with regard to diagnosis.

The EuroHeart Failure Survey [13,14] is the largest investigation focusing on the diagnosis and treatment of heart failure patients. The Austrian data have been shown to be representative of the data for Europe [13,14]. Using this data, we compared the sensitivity of the three peptides, BNP, N-BNP and N-ANP, with regard to potential differences in diagnosis. Since we have no information about outcome in patients with false negative values, patients were followed for up to 47 months to obtain mortality data.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
Three Austrian centers participated in the EuroHeart Failure Survey (one university hospital and two community hospitals). The protocol has been described in detail elsewhere [13]. In short, all patients diagnosed with heart failure in the participating hospitals were included. Heart failure was defined as; any kind of recorded diagnosis of heart failure within the last 3 years, current admission for heart failure, diuretic treatment for reasons other than renal failure, or any heart failure treatment. Patients were evaluated for co-morbidity, diagnostic features, pharmacological treatment, and in-hospital mortality. Up to three months for follow-up rehospitalization and mortality were documented.

At the end of the survey (3 months after discharge), all patients in the Austrian centers were invited to participate in a sub-study, which included the determination of neurohormone levels in blood. Patients had to give written informed consent to being followed-up for re-hospitalization and long-term survival. Of 347 patients, 112 were willing to participate in the sub-study.

Outcome was defined as mortality after the index evaluation. The extended observation period was 47 months.

2.1. Neurohumoral measurements
At the index evaluation, blood samples were drawn from an antecubital vein. The samples were centrifuged, transferred into chilled tubes, and placed on ice. Plasma was frozen at –20 °C until it was assayed. Natriuretic peptides (by ELISA) were determined using the following commercially available kits: BIOMEDICA, Austria for N-ANP, Biosite Diagnostics, San Diego, USA, for BNP (by ELISA) and Elecsys, Roche Diagnostics for N-BNP.

The normal values defined by the respective manufacturers were used as follows: for N-ANP <1980 pg/ml, for BNP <100 pg/ml. Values for N-BNP were dependant on age and sex as follows: females below 50 years <153 pg/ml, females above 50 years <334 pg/ml, males below 50 years <88 pg/ml and males above 50 years <227 pg/ml.

2.2. Outcome evaluation
The patients either visited our out-patient unit or were contacted by telephone to determine their survival status.

2.3. Statistics
Continuous variables are expressed as means±standard deviation. For group comparisons of continuous variables, a two-tailed Student's t-test was used. Patients were grouped according to survival after 3 years. Categorical variables were evaluated with Fisher's exact test. Median and normal levels of the neurohormones were used as cut-off points.

Kaplan–Meier survival analysis and the log-rank test were used to compare survival over time between patients with neurohumoral levels lower than or above the median level.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
Of 341 patients in Austria who participated in the EuroHeart Failure survey, 112 were included in this sub-analysis. All patients gave written informed consent. Detailed demographic and treatment data for the 341 patients have been previously published [13,14]. There were no significant differences between the selected 112 patients and the total cohort. The selected group comprised 71 males with a mean age of 68±12 years; 72% of patients received an ACE inhibitor and 51% a beta-blocker. The mean heart rate was 74±15 bpm, mean systolic blood pressure was 135±26 mm Hg and mean diastolic pressure was 74±13 mm Hg.

3.1. Neurohormones
Baseline levels of the neurohormones were as follows: N-ANP 13576±14723 fmol/ml, N-BNP 2562±4618 pg/ml and BNP 346±331 pg/ml. Median levels were 964 pg/ml for N-BNP, 231 pg/ml for BNP and 7358 fmol/ml for N-ANP.

3.1.1. Sensitivity of neurohormones
Normal N-BNP levels were found in 25% of patients, and normal BNP values in 30% of patients. N-ANP was considered normal in 5% of patients.

3.1.2. Analysis of patients with documented information about systolic or diastolic dysfunction
Echocardiography or ventriculography was not performed in 10 patients and 46 patients had no information reported about either systolic or diastolic dysfunction. Of the 56 patients with documented systolic or diastolic dysfunction, 23%, 27% and 5%, had normal levels of N-BNP, BNP and N-ANP, respectively. Systolic dysfunction was reported in 5, 8 and 1 patients with normal values of N-BNP, BNP and N-ANP respectively. Diastolic dysfunction was diagnosed in the remaining patients. Only 2 patients out of 112 were positively documented as having normal systolic and diastolic function.

3.1.3. Survival
Patients with normal N-ANP levels had a 100% survival rate over the observation period of 43 months. One of twenty-eight patients with normal N-BNP values died (after 28 months) and 2 of 34 patients with normal BNP levels died (after 23 and 28 months).

3.1.4. Risk stratification by neurohormones
Outcome at neurohormone levels between normal and lower median was as follows: 9% mortality for N-BNP, 7% for N-ANP and 7% for BNP. Long-term survival for patients with neurohumoral levels above the cut point (median) was 49% for N-BNP, 51% for N-ANP and 50% for BNP.

3.2. Kaplan–Meyer Analysis
The Kaplan–Meyer analysis for BNP; N-BNP and N-ANP showed differences between patients with values above and below the median levels. The differences were statistically significant for all hormones after 3 months (p<0.04), 6 months (p<0.01), 1 year (p<0.0001), 2 years (p<0.0001) and throughout the observation period (p<0.0001). (Fig. 1).


Figure 1
View larger version (14K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Kaplan–Meyer life time analysis according the median levels of BNP, N-BNP and N-ANP.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
This is the first study investigating the neurohormones N-ANP, N-BNP and BNP in a representative population from European hospitals. Our data reveal that the three neurohormones are comparable for risk stratification and clinical use. More importantly, the data reveal a remarkable difference in false negative values in patients with heart failure. This fact has significant implications for the use of the test.

4.1. Neurohormones and diagnosis
N-ANP, N-BNP and BNP have been shown to be good tests for the diagnosis of heart failure. N-ANP, most commonly investigated in mild to moderate heart failure, has also been shown to be very sensitive for predicting worse outcome in patients with preserved left ventricular function [2,3]. A direct comparison of BNP and N-ANP [4] in consecutive primary care patients revealed that both hormones were comparable with regard to the diagnosis of heart failure. BNP appeared to be somewhat better than N-ANP. However, it has to be taken into account, that heart failure was defined by an ejection fraction below 30%. Thus, patients with mild LVSD (ejection fraction between 30% and 55%) were not considered to have heart failure and were therefore excluded from the analysis. Moreover, diastolic dysfunction was not investigated. Acute dyspnea can be diagnosed by measuring BNP and N-BNP [8]. A recent study by Lainchbury investigated BNP and N-BNP in a head-to-head analysis [8]. The authors concluded that the two neurohormones differ in terms of sensitivity and specificity. In particular, sensitivity ranges between 94% for BNP (Biosite) and 80% for N-BNP (Roche). Tang found that 21% of patients with symptomatic heart failure have false negative BNP values [12]. Our data confirm the results of Tang and reveal the same problem of false negative values for N-BNP as well.

The reason for false negative values cannot be clarified from our data. One explanation could be, that heart failure therapy might normalize increased natriuretic peptides. But, patients who are at the highest risk for heart failure are patients with concomitant diseases such as hypertension, CAD or diabetes. ACE inhibitors and beta-blockers are an established therapy even in those patients independent of LV function. Consequently, the risk for misdiagnosis is increased. Another explanation might be the high number of patients with isolated diastolic dysfunction in our study population. Our subanalysis of patients with documented echocardiography shows that heart failure with diastolic dysfunction accounts for the majority of the patients with normal natriuretic peptide levels. Although natriuretic peptides are usually increased in this population, values were lower compared to patients with LVSD [8]. Nevertheless, it has to be taken into account, that short-term survival is comparable for patients with LVDD and LVSD [15].

To increase sensitivity, it may be argued that cut points could be lowered to subnormal values, as has been done by Sim [16] and Nielsen [17]. This increases the sensitivity to nearly 100% and makes the test more reliable. Although both studies demonstrated the cost-effectiveness of BNP compared to echocardiography even with the low cut points, the prevalence of false positive values and the costs of screening are much higher. The consequence of higher cut points, which would cause some heart failure patients to be misdiagnosed as false negative, is a delay in treatment, which may be followed by fatal events. Out data show a very low mortality rate in patients with hormone levels below the normal values. Besides, death occurs late. In our elderly population, mortality in those with normal N-ANP levels was zero after an observation period of 43 months. However, even patients with normal values of N-BNP and BNP had a low (4% and 6%, respectively) and late (23 and 28 months, respectively) mortality. Nevertheless, early treatment improves the long-term outcome and this favors the use of N-ANP for early diagnosis.

4.2. Neurohormones and risk stratification: +
Risk stratification by neurohormones has been more extensively investigated than diagnosis. In particular, it has been shown that N-ANP, BNP and N-BNP are superior to other predictors of outcome.

Comparisons between studies are rendered difficult by the fact that study designs and populations differ. Berger [18] demonstrated that the value of neurohormones in direct comparison depends, at least in part, on the clinical stage and the time of follow-up. Thus, depending on the conditions of the study and the statistics, the superiority of neurohormones may be ranked differently [1,5,7,9]. Our data, based on a typical clinical population, show that the three neurohormones are comparable in respect of risk stratification. Based on the median levels of the neurohormones, the long-term event rate, defined as mortality, is nearly equal, ranging between 49% and 51% in patients with above-median values. Moreover, the outcome over time is significant for all three hormones after 3 months and remains statistically significant over the entire observation period.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
Our data imply that N-ANP, N-BNP and BNP are comparable in their power to predict outcome in a typical clinical cohort. Furthermore, the hormones are distinctly different in terms of sensitivity for diagnosis, with N-ANP showing the lowest rate of false negative results. Nevertheless, all three neurohormones may be safely used to diagnose heart failure.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

  1. Hulsmann M., Berger R., Sturm B., Bojic A., Woloszczuk W., Bergler-Klein J., et al. Prediction of outcome by neurohumoral activation, the six-minute walk test and the Minnesota living with heart failure questionnaire in an outpatient cohort with congestive heart failure. Eur. Heart. J. (2002 (Jun)) 23(11):886–891.[Abstract/Free Full Text]
  2. Andersson B., Hall C. N-terminal proatrial natriuretic peptide and prognosis in patients with heart failure and preserved systolic function. J. Card. Fail. (2000) 6(3):208–213.[CrossRef][Web of Science][Medline]
  3. Hall Ch., Rouleau J., Moye L., Champlain J., Bichet D., Klein M., et al. N-terminal proatrial natriuretic factor. Circulation (1994) 89:1934–1942.[Abstract/Free Full Text]
  4. McDonagh T.A., Robb S.D., Murdoch D.R., Morton J.J., Ford I., Morrison C.E., et al. Biochemical detection of left-ventricular systolic dysfunction. Lancet (1998 (Jan 3)) 351(9095):9–13.[CrossRef]
  5. Berger R., Huelsmann M., Strecker K., Bojic A., Moser P., Stanek B., et al. B-type natriuretic peptide predicts sudden death in patients with chronic heart failure. Circulation (2002 (May 21)) 105(20):2392–2397.[CrossRef]
  6. McDonagh T., Holmer S., Raymond I., Luchner A., Hildebrant P., Dargei H. NT-pro BNP and the diagnosis of heart failure: a pooled analysis of three epidemiological studies. Eur. J. Heart Fail. (2004) 6:269–273.[Abstract/Free Full Text]
  7. Richards A., Nicholls G., Yandle T., Frampton C., Espiner E., Turner J., et al. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin. Circulation (1998) 97:1921–1929.[Abstract/Free Full Text]
  8. Lainchbury J., Campbell E., Frampton C., Yandle T., Nicholls M., Richards A. 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) 42:728–735.[Abstract/Free Full Text]
  9. Pfister M., Scholz M., Wielkens K., Erdmann E., Schneider C. Use of NT-pro BNP in routine testing and comparison to BNP. Eur. J. Heart Fail. (2004) 6:289–293.[Abstract/Free Full Text]
  10. Seino Y., Ogawa T., Yamashita T., Fukushima M., Ogata K., Fukumoto H., et al. Application of NT-pro BNP and BNP measurements in cardiac care: a more discerning marker for the detection and evaluation of heart failure. Eur. J. Heart Fail. (2004) 6:295–300.[Abstract/Free Full Text]
  11. Loke I., Squire I., Davies J., Ng L. Reference ranges for natriuretic peptides for diagnostic use are dependent on age, gender and heart rate. Eur. J. Heart Fail. (2003) 5:599–606.[Abstract/Free Full Text]
  12. Tang W., Girod J., Lee M., Starling R., Young J., Van Lente F., et al. Plasma B-type natriuretic peptide levels in ambulatory patients with established chronic symptomatic heart failure. Circulation (2003) 108:2964–2966.[Abstract/Free Full Text]
  13. Packer M. Should B-type natriuretic peptide be measured routinely to guide the diagnosis and management of chronic heart failure. Circulation (2003) 108:2950–2953.[Free Full Text]
  14. Cleland J., Swedberg K., Follath F., Komajda M., Cohen-Solal A., Aguilar J., et al. On behalf of the study group of diagnosis of the working group on heart failure of the European Society of Cardiology the EuroHeart Failure Survey Programme—a survey on the quality of care among patients with heart failure in Europe. Part 1: patient characteristics and diagnosis. Eur. Heart J. (2003) 24:422–463.
  15. Komajda M., Follath F., Swedberg K., Cleland J., Aguilar J., Cohen-Solal A., et al. On behalf of the study group of diagnosis of the working group on heart failure of the European Society of Cardiology the EuroHeart Failure Survey Programme—a survey on the quality of care among patients with heart failure in Europe. Part 2: treatment. Eur. Heart J. (2003) 24:464–474.[Abstract/Free Full Text]
  16. Lenzen M., Scholte O.P., Reimer W., Boersma E., Vantrimpont P., Follath F., et al. Differences between patients with a preserved and a depressed left ventricular function: a report from the EuroHeart Failure Survey. Eur. Heart J. (2004) 25:1214–1220.[Abstract/Free Full Text]
  17. Sim V., Hampton D., Phillips C., Lo S., Vasishta S., Davies J., et al. The use of brain natriuretic peptide as a screening test for left ventricular dysfunction-cost-effectiveness in relation to open access echocardiography family. Practice (2003) 20:570–574.
  18. Nielsen O., McDonagh T., Robb S., Dargie H. Retrospective analysis of the cost-effectiveness of using plasma brain natriuretic peptide in screening for left ventricular systolic dysfunction in the general population. J. Am. Coll. Cardiol. (2003) 41:113–120.[Abstract/Free Full Text]
  19. Berger R., Strecker K., Hulsmann M., Moser P., Frey B., Bojic A., et al. Prognostic power of neurohumoral parameters in chronic heart failure depends on clinical stage and observation period. J. Heart Lung Transplant. (2003) 22:1037–1045.[CrossRef][Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Hülsmann, M.
Right arrow Articles by Pacher, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hülsmann, M.
Right arrow Articles by Pacher, R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?