Field of Natriuretic-Peptide Markers for Acute Heart-Failure Diagnosis May Grow

September 10, 2008

September 10, 2008 (Munich, Germany) — Another biomarker in the natriuretic peptide family may be in the offing for helping with the emergency-department diagnosis of acute heart failure. A prospective study has concluded that, in that setting, an assay for the mid-regional fragment of atrial natriuretic peptide (ANP) prohormone (MR-proANP) is noninferior to the well-established test for B-type natriuretic peptide (BNP) [ color="blue">1].

Moreover, the newer test appears to add independent information to what is available from the currently used assays for BNP and the comparable N-terminal BNP prohormone (NT-proBNP) in some patient subgroups, for whom the latter tests are less conclusive, concluded researchers at the European Society of Cardiology Congress 2008.

"The story's not closed on BNP and NT-proBNP as the only two diagnostic markers that should be used for heart failure," Dr Alan S Maisel (University of California, San Diego) told heartwire .

The instability of ANP itself makes it unsuitable as a diagnostic marker, he said. "We've all known for years that ANP goes up in the blood in heart failure, but you just couldn't measure it. The cool thing about this prohormone fragment is that it has a correlation with ANP activity in vivo and ex vivo and is very stable. . . . This marker works just as well as the other peptides and may be complementary because in some cases the others don't work as well."

One of the findings from the Biomarkers in Acute Heart Failure (BACH) trial, which Maisel reported here, is that MR-proANP may add to the diagnostic power of BNP and NT-proBNP in patients with mid-range levels of those two peptides, which, he said, can be difficult to interpret. Such "gray-area" patients, he said, can make up more than a third of the dyspnea patients evaluated in the emergency department. The addition of MR-proANP testing to the evaluation would cut the size of that that group by about 30%, Maisel said.

A similar added benefit was seen in other types of dyspneic patients who are hard to pin down with BNP and NT-proBNP, he said. These included the very elderly, the obese, and those with renal dysfunction.

All that suggests that a test for multiple peptides would be more accurate than any single-marker test, according to Maisel. "We haven't done this, but it's possible that some [group] could put together [a test] for a couple of these neurohormones; then we could really tease out the gray-area patients for whom BNP doesn't work well," he said.

"I think this study is very much in vogue with the multimarker approach that's emerging for the diagnosis of heart failure and acute coronary syndromes, and I think it leaves us with some questions to answer going on from here," said discussant Dr Theresa A McDonagh (Royal Brompton & Harefield NHS Trust, London, UK) after Maisel presented the BACH trial.

"What we do know about natriuretic peptides in the emergency-room setting from three randomized, controlled studies is that they seem to reduce costs in terms of length of stay, lower readmission rates, and reduced time to discharge," she said. Now that MR-proANP has been shown to be "equivalent" to BNP and NT-proBNP, "What would be the extra cost of adding MR-proANP to BNP in the emergency-room setting, and would that additional cost justify these modest gains in diagnostic benefit?" Also, she asked, "Will it predict prognosis as well as BNP in acute heart failure?"

Maisel said to heartwire that another BACH analysis, to be presented at a future meeting, is comparing the prognostic capabilities of MR-proANP and BNP in the trial.

BACH entered 1636 patients evaluated in the emergency department for dyspnea without an obvious cause at 15 centers in the US, Europe, and New Zealand, of whom 567 received a final diagnosis of heart failure.

Table 1. Comparison of MR-proANP and BNP as maRkers for Heart Failure in the Emergency-Department Evaluation of Dyspnea

Parameter Sensitivity (%) Specificity (%) Diagnostic Accuracy (%)
MR-proANP >120 pmol/L 95.6 59.9 72.6
BNP >100 pg/mL 97.0 61.9 73.5
p for noninferiority <0.0001 <0.0001 <0.0001

MR-proANP=mid-regional fragment of atrial natriuretic peptide prohormone; BNP=B-type natriuretic peptide

Results for the two tests were highly correlated (r=0.919, p<0.001); positive test results were defined as >120 pmol/L for MR-proANP and >100 pg/mL for BNP. Using those cut points, the two tests were comparable--well within the 10% difference that was the prespecified limit for noninferiority, Maisel noted--with respect to sensitivity, specificity, and diagnostic accuracy for acute heart failure.

In a secondary analysis, both markers were independently predictive of heart failure. "When you control for MR-proANP, BNP does add complementary information. And vice versa--if you control for BNP, you can still get a lot of diagnostic information from MR-proANP," Maisel said in his presentation.

Table 2. Odds Ratio (OR) of MR-proANP and BNP for Heart Failure in Multivariate Analysis

Predictor OR (95% CI) p
MR-proANP >120 pmol/L 11.53 (6.46–20.57) <0.0001
BNP >100 pg/mL 7.55 (4.59–12.41) <0.0001

MR-proANP=mid-regional fragment of atrial natriuretic peptide prohormone; BNP= B-type natriuretic peptide.

MR-proANP was significantly more diagnostic than BNP and NT-proBNP in patients with the mid-range readings for the latter peptides and a few patient subgroups. For example, it was more diagnostic than BNP in obese patients (p=0.019) and in those with BNP readings >100 to <500 pmol/mL (p=0.002). And it was more diagnostic than NT-proBNP in patients with readings for that peptide of >30 to <900 (p=0.005) and in those with elevated creatinine (p<0.001), the obese (p=0.001), and those 70 years or older (p=0.001) or with edema (p=0.002).

The investigational MR-proANP diagnostic test is made by Brahms Diagnostics; the test for BNP is available from Biosite; and tests for NT-proBNP are available from Roche Diagnostics and bioMérieux.

Maisel disclosed that he has received research support from Brahms Diagnostics, Roche Diagnostics, Abbott Healthcare, Biosite, and Siemens.

  1. Maisel AS. Results from the BACH (Biomarkers in Acute Heart Failure) Trial. European Society of Cardiology Congress 2008; September 2, 2008; Munich, Germany. Clinical trials update 2.

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