For proven natriuretic peptides, still much to be learned

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Dr. Daniels

BNP and NT-proBNP might also be the Kansas City of biomarkers: one in Missouri, one in Kansas; both important, useful, and perhaps semi-indistinguishable. “They’re very highly correlated,” says cardiologist Lori Daniels, MD, “and overall they’re very, very comparable. Obviously, you can’t interchange values, and you have to learn to use each of them, because they have separate cutpoints.” Both have gray zones as well—and, correspondingly, neither should be seen as a standalone test. “Even someone with a ‘diagnostic’ level has to be put into a clinical context,” she says. “But both tend to be very similar for both prognosis and diagnosis.”

One important difference is emerging, however, in patients being treated with the new therapeutic heart failure medication Entresto (approved by the FDA in early July). The drug contains a neprilysin inhibitor, which causes BNP to rise. “Neprilysin is one of the ways that BNP is cleared from circulation,” Dr. Januzzi explains. If physicians use serial measurements of BNP to assess risk and make therapy decisions based on those levels in a patient receiving Entresto, “It’s going to make interpretation of BNP extremely challenging, particularly in the chronic outpatient setting,” he says. “Laboratorians need to be well aware of the fact that this new therapy may cause some confusion.”

While clinicians are becoming cognizant of this, Dr. Januzzi says, “I think education is critically important at this stage, because the drug is expected to be widely used for heart failure therapy in the years to come.”

Laboratories have a role to play here, he continues. With the emergence of neprilysin inhibition, Dr. Januzzi says, “I suspect that labs are going to sit up and take notice about the potential risk for a false attribution of decompensation of heart failure when a patient is taking Entresto.” Even more worrisome, he says, is the potential harm to the patient if a clinician misinterprets a rise in BNP as being decompensation, then intensifies therapy to try to lower the BNP value. “When in fact the rise in BNP is favorable, related to the effects of the drug.” It’s critical for laboratory specialists in particular to understand this issue, he says, because they are often the first person clinicians will contact when they receive a confusing lab result. “To the extent that they can lead, this needs to be in their consciousness.”

“Lead” might be the operative word whenever laboratories weigh in on using NT-proBNP or BNP. As Dr. Daniels has learned, “impose” is unlikely to work.

At the University of California San Diego’s Division of Cardiology, where Dr. Daniels is director of the coronary care unit and professor of medicine, the laboratory switched from using BNP to NT-proBNP. “It wasn’t a clinical decision,” she says.

The change didn’t go smoothly, she recalls, “because the switch was already made before they got buy-in from any cardiologist. That caused a lot of tension.” At one point laboratory directors attended a meeting of the cardiology faculty. “It didn’t go as well as it could have, because a lot of the cardiologists felt they were being told they had to make a switch, rather than being brought along early in the decision-making process.”

That’s when the laboratory took a step back and began working more closely with cardiologists. It brought in educational speakers to talk about the new marker, and the laboratory and cardiologists developed a plan to make both markers available during a transition period. This gave the cardiologists time to learn how to use it and to transition their patients more smoothly, Dr. Daniels says. A quality assurance step—measuring both markers in 500 consecutive patients, with outcomes follow-up—also helped. “We could ensure that the new marker was at least as good as what we had been using,” Dr. Daniels recalls.

Clinicians can still order BNP, but NT-proBNP is the default, and turnaround time for the latter (which is done in hospital) is faster than BNP (which is sent to a central laboratory). “For the most part we’re using pro-BNP,” Dr. Daniels says, though BNP will still be ordered for patients who’ve only had BNP measurements. “We’d need that to compare. But then hopefully we’d transition over to proBNP—just because it’s more cost-effective for our patients at this point.”

The two tests are similar in many settings. “Just to be clear, anywhere you would use BNP, one would also use proBNP,” says Dr. Daniels. At her institution, that includes using it diagnostically and prognostically in the ED for heart failure patients; to monitor progression in patients admitted with acute decompensated heart failure; to establish predischarge prognosis. “And in the clinics we’re also using it to help assess volume status and help with the titration of cardiovascular medication.”

Physicians are paying close attention to 30-day readmission rates. “There’s good data out there that people with elevated concentrations of proBNP or BNP are at increased risk for 30-day readmissions for heart failure,” Dr. Daniels says. “We are starting to use that in an informal way—just before someone leaves, you get a level. If it’s really high, either a) we reassess their volume status and try to get them more euvolemic, or b) if we can’t—because they are already euvolemic and that’s just what their baseline natriuretic peptide concentration is—we try to get them into our heart failure clinic within a week.” On a more formal level, she adds, she and her colleagues are trying to develop an algorithm—one incorporating NT-proBNP—to predict readmission risk.

She’s also intrigued by studies that show BNP and NT-proBNP may help guide therapy, including data from the PROTECT study (headed by Dr. Januzzi), in which NT-proBNP was used in the outpatient setting. By targeting a level of <1,000 pg/mL, researchers were able to reduce the primary endpoint, which was a composite outcome that included rehospitalization for heart failure. They did so by getting patients on higher doses of guideline-recommended therapy.
That may be somewhat controversial, she concedes. “People say that if it’s guideline-directed therapy, patients should be on it anyway. Which is true,” she says. “But studies show we’re not so good at that, and having that number to target [proBNP <1,000 pg/mL] gives us an impetus to push it a little bit more and get them on those higher doses of cardioprotective meds.”

At Massachusetts General Hospital, Dr. Januzzi and his colleagues have started remeasuring patients’ natriuretic peptide values at time of discharge. If levels have not dropped by 30 percent, which seems to be the point that identifies risk in acute heart failure, he says, “we typically view that patient as being at higher risk for rehospitalization.” Such patients will either be kept in the hospital longer or enrolled in a more aggressive postdischarge management strategy.

“It stands to reason that if these markers rise and fall like a barometer with respect to response to therapy,” Dr. Januzzi says, “if they have not fallen substantially by the time we feel discharge is ready, it’s likely we’re missing something clinically. And that patient is likely to be a higher-risk patient.” Since it’s neither desirable nor possible to keep all patients hospitalized longer, nor feasible to refer everyone for more aggressive postdischarge care, natriuretic peptides might help winnow the list.

If it’s not clear by now, there’s still much to be learned about BNP and NT-proBNP. “We know there is a substantial amount of post-translational modification of both peptides,” Dr. Januzzi says. NT-proBNP, for example, has varying degrees of glycosylation that may interfere with its recovery in clinically used assays. “So we need a better understanding regarding the clinical as well as laboratory meaning of all these unusual modifications of NT-proBNP as
well as BNP.”

“It doesn’t mean the tests shouldn’t be used clinically,” he hastens to add. Their value has been proven. “But as with any diagnostic or prognostic that we use, our understanding of the test evolves.” Deeper knowledge of the natriuretic peptides can only be of value, because the heart releases these peptides as a way to compensate for heart failure. “Understanding the disease of heart failure may also shed light on new ways to manage patients.”

Karen Titus is CAP TODAY contributing editor and co-managing editor.