• Apple FS, Wu AH, Jaffe AS, Panteghini M, Christenson RH, Cannon CP, Francis G, Jesse RL, Morrow DA, Newby LK, Storrow AB, Tang WH, Pagani F, Tate J, Ordonez-Llanos J, Mair J, National Academy of Clinical Biochemistry, IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory. National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine practice guidelines: Analytical issues for biomarkers of heart failure. Circulation 2007 Jul 31;116(5):e95-8. [30 references] PubMed



• Writing Group Members, Apple FS, Wu AH, Jaffe AS, Panteghini M, Christenson RH, NACB Committee Members, Christenson RH, Apple FS, Cannon CP, Frances GS, Jesse RL, Morrow DA, Newby LK, Storrow AB, Tang WH, Wu AH, IFCC Committee on Standardization of Markers of Cardiac Damage (C-SMCD) Members, Apple FS, Cannon CP, Jaffe AS, Pagani F, Tate J, Ordonez-Llanos J, Mair J. National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine practice guidelines: analytical issues for biomarkers of heart failure. Clin Biochem 2008 Mar;41(4-5):222-6. [30 references] PubMed

This guideline updates a previous version: Wu AH, Apple FS, Gibler WB, Jesse RL, Warshaw MM, Valdes R Jr. National Academy of Clinical Biochemistry Standards of Laboratory Practice: recommendations for the use of cardiac markers in coronary artery diseases. Clin Chem 1999 Jul;45(7):1104-21. [119 references] PubMed

• Chapter 1: Clinical characteristics and utilization of biochemical markers in acute coronary syndromes
• Chapter 2: Analytical issues for biochemical markers of acute coronary syndromes
• Chapter 3: Clinical utilization of cardiac biomarker testing in heart failure
• Chapter 5: Point of care testing, oversight and administration of cardiac biomarkers for acute coronary syndromes
• Chapter 6: Use of cardiac troponin and B-type natriuretic peptide or N-terminal proB-type natriuretic peptide for etiologies other than acute coronary syndromes and heart failure

Analytical Biomarker Issues

Issues Related to B-type Natriuretic Peptide (BNP) and N-Terminal pro-BNP Natural Peptide (NT-proBNP) Measurement

Recommendations for analysis of biochemical markers of heart failure

Class I

1. Before introduction into clinical practice, BNP and NT-proBNP assays must be characterized with respect to the following preanalytical and analytical issues.

   Preanalytical:

   1. Sample type; including type of biological sample: serum, plasma, whole blood; and type of specimen collection tubes
   2. Effect of storage time and temperature

   Analytical:

   1. Identification of antibody recognition epitopes
   2. Description of calibration material used; with identification of source and the concentration value assignment. Until a clear determination of the clinically relevant molecules is established and a corresponding reference system is defined, results for both BNP and NT-proBNP should be reported in micrograms/L, rather than pmol/L.
   3. Determination of cross reactivity characteristics with related natriuretic peptides (NPs), especially for BNP, NT-proBNP and proBNP, as well as for, atrial natriuretic peptide, NT-proANP, C-type natriuretic peptide
   4. Evaluation of dilution response
   5. Evaluation of interferences such as heterophile antibodies, rheumatoid factors, human antimouse antibodies (Level of Evidence: C)

2. Upper reference limits, at the 97.5th percentile of the reference value distribution, should be independently established for both BNP and NT-proBNP based on age, by decade, and by gender. Each commercial assay should be validated separately. (Level of Evidence: C)
3. Patients specimen comparisons and regression analysis should be performed, along Clinical and Laboratory Standards Institute (CLSI) (formerly the National Committee for Clinical Laboratory Standards [NCCLS]) guidelines, to establish the degree of or lack of harmonization across the dynamic range of each assay. Harmonization has been proposed around the current presumed optimal diagnostic medical decision cutoff for heart failure of 100 micrograms/L for BNP, as found in the Breathing Not Properly Trial using the Biosite assay (Maisel et al., 2002). This may not be ideal for other nonheart failure clinical situations. More formal harmonization efforts might well be necessary along the lines done for other analytes, i.e., cardiac troponin and creatine kinase MB. Since there is only one source of antibodies and calibrators for NT-proBNP (Roche), harmonization of NT-proBNP assays should not be a problem. (Level of Evidence: C)
4. Receiver operating characteristic (ROC) curves should be established to evaluate the clinical effectiveness and to establish optimal medical decision cutoffs for both BNP and NT-proBNP assays for diagnostic usefulness. Data need to be reported in concentration numbers to allow for consensus between assays and not only in quartiles and tertiles. (Level of Evidence: C)

Class IIa

1. Assays for BNP and NT-proBNP should have a total imprecision (% coefficient of variation [CV]) of <15% at concentrations corresponding to their age and gender defined upper reference limits. (Level of Evidence: C)
2. The effect of ethnicity needs to be evaluated as a possible independent variable. (Level of Evidence: C)
3. Caution should be exercised in interpreting <50% concentration changes as being related to medical therapy because a consistently high biological variation for both BNP and NT-proBNP exists. However, consistent trends should be followed as clinically important. (Level of Evidence: B)

Definitions:

Weight of Evidence

A - Data derived from multiple randomized or appropriately designed clinical trials that involved large numbers of patients

B - Data derived from a limited number of randomized or appropriately designed trials that involved small numbers of patients or from careful analyses of observational registries

C - Expert Consensus was the primary basis for the recommendation

Summary of Indications

Class I: Conditions for which there is evidence and/or general agreement that a given laboratory procedure or treatment is useful and effective.

Class II: Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a laboratory procedure or treatment.

Class IIa: Weight of evidence/opinion is in favor of usefulness/efficacy.

Class IIb: Usefulness/efficacy is less well established by evidence/opinion.

Class III: Conditions for which there is evidence and/or general agreement that the laboratory procedure/treatment is not useful/effective and in some cases may be harmful.

References open in a new window

• Apple FS, Wu AH, Jaffe AS, Panteghini M, Christenson RH, Cannon CP, Francis G, Jesse RL, Morrow DA, Newby LK, Storrow AB, Tang WH, Pagani F, Tate J, Ordonez-Llanos J, Mair J, National Academy of Clinical Biochemistry, IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory. National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine practice guidelines: Analytical issues for biomarkers of heart failure. Circulation 2007 Jul 31;116(5):e95-8. [30 references] PubMed



• Writing Group Members, Apple FS, Wu AH, Jaffe AS, Panteghini M, Christenson RH, NACB Committee Members, Christenson RH, Apple FS, Cannon CP, Frances GS, Jesse RL, Morrow DA, Newby LK, Storrow AB, Tang WH, Wu AH, IFCC Committee on Standardization of Markers of Cardiac Damage (C-SMCD) Members, Apple FS, Cannon CP, Jaffe AS, Pagani F, Tate J, Ordonez-Llanos J, Mair J. National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine practice guidelines: analytical issues for biomarkers of heart failure. Clin Biochem 2008 Mar;41(4-5):222-6. [30 references] PubMed

All potential conflicts of interest for the NACB guidelines committee and ad hoc members of the writing committees are listed at the following: http://www.aacc.org/AACC/members/nacb/LMPG/OnlineGuide/PublishedGuidelines/ACSHeart/heartpdf.htm.

This guideline updates a previous version: Wu AH, Apple FS, Gibler WB, Jesse RL, Warshaw MM, Valdes R Jr. National Academy of Clinical Biochemistry Standards of Laboratory Practice: recommendations for the use of cardiac markers in coronary artery diseases. Clin Chem 1999 Jul;45(7):1104-21. [119 references] PubMed

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Electronic copies: Available from the National Academy of Clinical Biochemistry (NACB) Web site.

Print copies: National Academy of Clinical Biochemistry publications are available through American Association for Clinical Chemistry (AACC) Press. To make a purchase or request a catalog, contact AACC Customer Service at 202-857-0717 or custserv@aacc.org.

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