CORRESPONDENCE: LETTER TO THE EDITOR
Biomarker Sensitivity and Specificity Require Pre-Test Probability of Disease Diagnosis to Be CollatedAdditional Points on the Interpretation of Pro–B-Type Natriuretic Peptide Triage of Dyspnea in the Copenhagen Heart Study
Robert J. MacFadyen, BSc, MD, PhD, FRCP* and
M. Jennyfer Ng Kam Chuen, MBBS, MRCP
* University Department of Medicine, City Hospital, Dudley Road, Birmingham B18 7QH, United Kingdom (Email: Robert.macfadyen{at}swbh.nhs.uk).
The Copenhagen City Heart study (1) provides important insight into community assessment of breathlessness. The report could be taken to support pro–B-type natriuretic peptide (proBNP) triage of all breathless patients in this setting. We feel this is a simplistic analysis of the potential contribution of biomarker technology and that a number of additional points should be considered.
The relationship of BNP measures to cardiac impairment has been confirmed, and their utility tested in a variety of settings (1,2). However, the sampling frame of most surveys (2,3) is of little relevance to the general practitioner. Importantly in the Copenhagen study, 48% of their breathless patients had neither cardiac nor pulmonary abnormality. In fact, the major causes of dyspnea in a population-based study were obesity, depression, and older age (4). Thus, even before addressing the performance of proBNP analysis, the authors must surely also address the relative diagnostic void that is presented for almost half of the patients in their study.
Secondly, the incremental value of proBNP testing is not clearly put in the context of clinical history; physical examination and simple bedside tests such as a 12-lead electrocardiogram and a chest roentgenogram. Although these may individually have low sensitivity and specificity and are operator specific (5,6), they contribute to pre-test diagnostic probability, which, in turn, affects the performance of any biomarker and the post-test probability of the presence of cardiac dysfunction (7). By excluding the contribution of the physician, the ability of the test to function cost-effectively could alternatively be compromised or enhanced. Thus, a dyspneic patient with a high proBNP level could undergo echocardiography, even in the absence of abnormalities on examination and bedside investigations. Surely in such patients resources would be better employed establishing a noncardiac cause for dyspnea.
Thirdly, although the authors accounted for age and gender, they need to interpret point measurement of proBNP levels with great care due to their large intraindividual and interindividual variability (33.3% and 36.5%, respectively, in normal individuals [8]). Both symptomatic and asymptomatic patients with stable systolic heart failure present with wide ranges of plasma BNP, with up to 21% of symptomatic patients having BNP levels below what would be considered "diagnostic"(9).
Finally, the concept that pulmonary disease can be defined by spirometry alone is not acceptable. This limited technique does not rule out the presence of significant parenchymal lung disease. Moreover, proBNP levels can be elevated in lung conditions resulting in right heart strain and pulmonary hypertension (10,11).
The authors are to be congratulated on their effort in challenging the use of biomarker technology for the community assessment of breathlessness. However, its commercial exploitation needs to be based on its cost-effectiveness and applicability to realistic clinical practice. It needs to be interpolated in the light of clinical assessment, particularly given the large percentage of true negative results for either cardiac or pulmonary abnormalities.
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1. Mogelvang R, Goetze JP, Schnohr P, et al. Discriminating between cardiac and pulmonary dysfunction in the general population with dyspnea by plasma pro-B-type natriuretic peptide J Am Coll Cardiol 2007;50:1694-1701.[Abstract/Free Full Text]2. McDonagh TA, Holmer S, Raymond I, Luchner A, Hildebrant P, Dargie HJ. NT-proBNP and the diagnosis of heart failure: a pooled analysis of three European epidemiological studies Eur J Heart Fail 2004;6:269-273.[Abstract/Free Full Text] 3. O’Donaghue M, Kenney P, Oestreicher E, et al. Usefulness of aminoterminal pro-brain natriuretic peptide testing for the diagnostic and prognostic evaluation of dyspneic patients with diabetes mellitus seen in the emergency department (from the PRIDE study) Am J Cardiol 2007;100:1336-1340.[CrossRef][Web of Science][Medline] 4. Azevedo A, Bettencourt P, Pimenta J, et al. Clinical syndrome suggestive of heart failure is frequently attributable to non-cardiac disorders—population-based study Eur J Heart Fail 2007;9:391-396.[Abstract/Free Full Text] 5. Androne AS, Hryniewicz K, Hudaihed A, et al. Relation of unrecognised hypervolaemia in chronic heart failure to clinical status, haemodynamics, and patient outcomes Am J Cardiol 2004;93:1254-1259.[CrossRef][Web of Science][Medline] 6. Chakko S, Woska D, Martinez H, et al. Clinical, radiographic, and haemodynamic correlations in chronic congestive heart failure: conflicting results may lead to inappropriate care Am J Med 1991;90:353-359.[Web of Science][Medline] 7. Black ER, Panzer RJ, Mayewski RJ, Griner PF. Characteristics of diagnostic tests and principles for their use in quantitative decision makingIn: Panzer RJ, Black ER, Griner PF, editors. Diagnostic Strategies for Common Medical Problems. Philadelphia, PA: American College of Physicians; 1991. pp. 1-16. 8. Wu AH, Smith A, Wieczorek S, et al. Biological variation for N-terminal pro- and B-type natriuretic peptides and implications for therapeutic monitoring of patients with congestive heart failure Am J Cardiol 2003;92:628-631.[CrossRef][Web of Science][Medline] 9. Tang WHW, Girod JP, Lee MJ, et al. Plasma B-type peptide levels in ambulatory patients with established chronic symptomatic systolic heart failure Circulation 2003;108:2964-2966.[Abstract/Free Full Text] 10. Pruszczyk P. N-terminal pro-brain natriuretic peptide as an indicator of right ventricular dysfunction J Card Fail 2005;11(Suppl):S65-S69.[CrossRef][Web of Science][Medline] 11. Leuchte HH, Baumgartner RA, Nounou ME, et al. Brain natriuretic peptide is a prognostic parameter in chronic lung disease Am J Respir Crit Care Med 2006;173:744-750.[Abstract/Free Full Text]
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