Beth Israel Deaconess Medical Center Laboratory Manual

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1. What are B-Type Natriuretic Peptides?
2. What's the relationship between BNP and NTproBNP?
3. Why did BIDMC choose NTproBNP?
4. What are the indications for using NTproBNP?
5. How good a test is NTproBNP?
6. What's a "normal" NTproBNP level?
7. What does an elevated NTproBNP level mean?
8. What constitutes a significant change in NTproBNP level?
9. How frequently should NTproBNP be measured?
10. Does renal failure cause elevations in NTproBNP?
11. How much does an NTproBNP measurement cost?
12. Are there guidelines about using NTproBNP in the Emergency Dept.?
13. Who do I contact for more information?

1. What are B-Type Natriuretic Peptides (BNPs)?

Originally called Brain Natriuretic Peptide because it was isolated from brain, this peptide hormone was later discovered to be produced by ventricles in response to increases in wall tension. Its name has been updated to B-type Natriuretic Peptide (as distinct from Atrial Natriuretic Peptide, ANP).

The circulating concentration for BNP is about 20% of ANP in normal subjects, but can exceed that of ANP in patients with heart failure. It is this responsiveness of BNP that makes it a valuable diagnostic tool in assessing the etiology of dyspnea of unknown etiology. B-Type Natriuretic Peptides are increased in patients with heart failure, and the levels increase in proportion to the degree of left ventricular dysfunction.

2. What is the relationship between BNP and NTproBNP?

The prohormone is proBNP, which is cleaved into two fragments upon release from cardiac muscle cells:

1. BNP, amino acids 77-108, the active hormone
2. NTproBNP, amino acids 1-76, the N-terminal fragment

Even though NTproBNP is physiologically inactive, its levels are highly correlated with BNP levels. Most experts agree that both peptides offer similar diagnostic information, but there are two differences to note.

First, the half-lives of the two proteins are slightly different:

• BNP ~ 20 minutes
• NTproBNP ~90 minutes.

Second, the two assays have different "cross-reactivities" with the therapeutic drug nesiritide (Natrecor), which is, in fact, recombinant BNP:

• BNP will detect nesiritide (i.e., it will detect nesiritide plus endogenous BNP)
• NTproBNP will not detect nesiritide at all

3. Why did BIDMC choose NTproBNP?

We chose NTproBNP for two major reasons, one clinical and the other practical.

• All NTproBNP assays are the same. You can read any reference in the literature, and the analytical results will be directly transferable to BIDMC.
  
  For BNP there are several different assays, each of which may have a different reference range.
  
• Second, from the practical perspective, we already have the instrumentation for NTproBNP. It's available on both the east and west campuses, and our techs are already proficient on it.
  

4. What are the indications for measuring NTproBNP?

There are at least 4 indications for ordering NTproBNP (or BNP):

1. Establishing the cause of shortness of breath in the ED, for example distinguishing between CHF and COPD.
   (e.g., Maisel et al, N Engl J Med 2002;347:161-7, or
   Lainchbury et al, J Am Coll Cardiol 2003;42:728-735)
2. Screening for CHF (especially, NYHA Grades I & II)
   (e.g., McDonagh et al, Lancet 1998;351:9-13)
3. Estimating CHF prognosis
   (e.g., Gardner et al, European Heart J, 2003;24:1735)
4. Monitoring the progress (or response to treatment) of CHF.
   (e.g., Troughton et al, Lancet 2000;355:1126-1130)

At BIDMC, we expect that the first indication will be the most frequent, at least to start.

For an excellent overall review of the literature on NTproBNP (and BNP), please see Munagala et al, Curr Probl Cardiol, 2004:29:707-769.

5. How good a test is NTproBNP?

NTproBNP (and BNP) have rapidly become widely used cardiac markers because they have excellent predictive values:

• When used to screen for CHF in an outpatient setting, the negative predictive values are reported as 98-99%. That is, a negative value can rule out CHF with a high level of certainty.
  
• When used in the Emergency Department to determine the cause of acute dyspnea, studies have shown that BNP/NTproBNP is the best predictor of CHF, exceeding by far chest x-ray and physical examination (e.g., Maisel et al, N Engl J Med 2002;347:161-7; Lainchbury et al, J Am Coll Cardiol 2003;42:728-735; Januzzi et al, PRIDE study, in press).

(In the Table below [from Maisel above], note that B-type natriuretic peptide is BNP, so the absolute value of 100 pg/mL is different from what the value would be for NTproBNP. The major point is, with an Odds Ratio of 30, elevated B-type natriuretic peptide was by far the best predictor for CHF.)

Nonetheless, not all patients with elevated NTproBNP levels will have CHF as the cause of their acute dyspnea. Patients with compensated CHF may present with acute dyspnea of non-cardiac etiology. Such patients will not have normal NTProBNP levels, but their elevated levels will be related to baseline disease.

6. What's a "normal" NTproBNP level?

Of note, reference ranges vary with gender and age. On average, women have higher values than men, and values in both genders increase with age. On each CCC report, the reference range listed will be tailored for the patient's gender and age.

For screening outpatients, the manufacturer recommends maximizing sensitivity (and negative predictive value) by using two thresholds based on age:

<125 pg/mL for patients younger than 75
<450 pg/mL for patients age 75 and older.

Note that, for simplicity, the manufacturer decided against gender-specific and additional age-specific cut-offs.

Using these thresholds and reasonable estimates of CHF prevalence, the Negative Predictive Value (NPV) is roughly 98%, and the Positive Predictive Value (PPV) is roughly 90%. Put differently, a normal NTproBNP effectively rules out CHF.

(For more detail on the test's performance using these thresholds, the chart below from the manufacturer's FDA submission gives the sensitivity, specificity, and negative predictive values by gender and age:

7. What does an elevated NTproBNP level mean?

As noted above, when screening outpatients, a normal NTproBNP effectively rules out CHF. In this population, an elevated NTproBNP would dictate follow-up testing with more definitive (specific) tests for CHF.

But what if you wanted to use this test in the ED to establish CHF as the cause of acute dyspnea? Should you use the same cut-offs?

Probably not. Even though a normal value still rules out CHF very effectively, a mildly elevated value may well be unrelated to the acute episode. Two studies cited earlier (Lainchbury et al, J Am Coll Cardiol 2003;42:728-735; Januzzi et al, PRIDE study, in press) have addressed this question, with comparable results. Data from one is summarized below:

In other words, as you raise the threshold, the positive predictive value increases (and the negative predictive value decreases). At a cut-off of 150 pg/mL, only 53% of the positive values would be true positives; at 1000 pg/mL, 78% are true positives. The higher the NTproBNP level, the more likely CHF is the cause of acute dyspnea.

As a result, we have decided to set 1000 pg/mL as our cut-off for CHF as a likely cause of dyspnea in patients presenting to the ED. At a CHF prevalence of 35% (as was the case in both studies), for every 4 patients with NTproBNP levels above 1000 pg/mL, 3 will have CHF as the etiology, and 1 will have another cause of dyspnea.

The Emergency Department has created a helpful flowchart regarding use of NTproBNP in the evaluation of Acute Dyspnea.

8. What constitutes a significant change in NTproBNP level?

The NTproBNP assay has excellent precision. If we were to run the same sample once daily for many days, the variation in the results would be less than 10%. That is, a sample with a value of 1000 pg/mL would be measured as 900-1100 pg/mL.

However, there's a large amount of physiologic, intra-individual variation. As a result, many experts recommend that changes of less than 2-fold not be considered significant. In other words, if the levels have not doubled or halved, then it should not be considered a real change.

9. How frequently should NTproBNP be measured?

Many authorities agree that NTproBNP (or BNP) should be measured no more often than once per week in any given patient. Real changes related to pathophysiology or therapy require time to occur. Although serial values can be very important, the cycle time is very different from cardiac troponins and CK-MB.

10. Does renal failure cause elevations in NTproBNP?

Renal failure causes mild elevations in NTproBNP (up to 300-500 pg/mL) in NTproBNP (Januzzi et al, PRIDE study, in press). Nonetheless, NTproBNP remains an excellent CHF marker in these patients.

11. How much does an NTproBNP measurement cost?

NTproBNP will be among the most expensive tests done in Clinical Chemistry. For comparison, the reagent cost for NTproBNP is 5 times that of cardiac troponin T and 15 times that of CK-MB.

For outpatients, we estimate that most payers will cover the cost of the test.

For inpatients, we get no additional payment for this test. In general, there is a standard payment for an admission, based on the discharge diagnosis, regardless of how many tests are done.

The bottom line is that you should order the test only when it will help you make good medical decisions for your patients.

12. Are there guidelines about using NTproBNP in the Emergency Dept.?

Yes, the Emergency Department has created a flowsheet regarding the use of NTproBNP in the evaluation of patients with acute dyspnea of unknown etiology.

13. Who should I contact for more information?

This document was authored by Drs. David Feinbloom, Kalon Ho, Gary Horowitz, and Larry Mottley. Please contact one of them for more information.

Last reviewed: 4/11/08