College of American Pathologists

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Clues pile up, suggesting broad BNP role

April 2004
William Check, PhD

Like the mythical Greek hero Hercules, B-type natriuretic peptide, or BNP, appears to have the ability to take on multiple daunting challenges and emerge victorious. It’s now established that measuring plasma BNP levels, in conjunction with clinical judgment, increases the ability to distinguish between congestive heart failure and noncardiac causes such as chronic obstructive pulmonary disease in patients presenting to the emergency department with acute shortness of breath. In addition to its use as a diagnostic tool in acute dyspnea—which a recently published study shows improves disease management and reduces cost—BNP is being explored also for risk stratification and disease monitoring.

"BNP is being used for risk stratification across the entire spectrum of heart disease," says James deLemos, MD, assistant professor of medicine at the University of Texas Southwestern Medical School, Dallas, and director of the coronary care unit at Parkland Hospital. The conditions in which BNP can aid in prognostic assessment are congestive heart failure, acute coronary syndromes, and diseases that involve the right side of the heart (pulmonary embolism, pulmonary hypertension, and congenital heart lesions). "The higher the BNP level, the greater the probability that the patient will die or deteriorate," Dr. deLemos says. A remaining issue is setting cutoffs. "This has not been fully worked out yet," he says. He adds, "There is no real cutoff because higher is worse in terms of prognosis."

In the view of Fred Apple, PhD, medical director of clinical laboratories at Hennepin County Medical Center, Minneapolis, and professor of laboratory medicine and pathology at the University of Minnesota School of Medicine, "Risk stratification has not been proven as an acceptable practice at present, pending the results of trials that may show an impact of therapy on risk-based BNP concentrations."

Dr. deLemos says the use of BNP for disease monitoring is an "emerging" application that has also not yet been proven. In this situation, BNP levels are measured serially over time and used as targets for therapy. "We want to get BNP as low as possible to improve outcomes in heart failure," he says. When BNP is used for monitoring in the hospital setting, a patient admitted with congestive heart failure would get a BNP reading at presentation and possibly again just prior to discharge to see whether therapy has been successful. Says Dr. Apple: "The patient might seem clinically improved, but if BNP triples that tells you something else. I doubt that a patient would be sent home under those circumstances."

Petr Jarolim, MD, PhD, director of clinical chemistry at Brigham and Women’s Hospital, Boston, agrees: "BNP helps to distinguish cardiogenic conditions from other conditions with similar symptoms such as chest pain and shortness of breath. While originally developed as a diagnostic test for heart failure, BNP or NT-proBNP levels can also predict outcomes in other conditions, such as pulmonary embolism. We have a cardiologist from Switzerland working here who published a study in 73 patients of NT-proBNP as a diagnostic tool and a predictor in suspected pulmonary embolism." Other cardiologists at Brigham and Women’s are interested in expanding that work.

Dr. Jarolim is doing BNP measurement for pilot studies or trials testing BNP as a predictor in various conditions, including acute coronary syndromes, or ACS, and pulmonary embolism, or PE, as well as for prognostication in congestive heart failure, or CHF. He says that during one recent two-week period four physician groups approached him to set up pilot studies for new applications for BNP. "It has been incredible," Dr. Jarolim says. "Just last Friday I had one morning and one afternoon meeting with investigators coming to find out whether they could send us specimens. We are definitely in a period of excitement when we are finding out how useful BNP actually is."

"In all areas [of BNP use] the learning curve is very steep," Dr. Apple says. "We are learning more about how to utilize this marker all the time. There is an overwhelming number of BNP-related articles published every week—both new applications and new understandings of old applications."

Like the seven labors of Hercules, each successive proposed use for BNP is more impressive than the last. A few months ago evidence was presented for the most sweeping potential indication so far: screening asymptomatic people to determine their risk of cardiovascular events and death. Despite the significant findings, Thomas Wang, MD, the first author on the publication, expresses caution. "We certainly need more data before knowing whether and how BNP should be used in people who are asymptomatic," says Dr. Wang, an instructor in cardiology at Massachusetts General Hospital, Boston, and an investigator in the Framingham Heart Study.

Differential diagnosis in patients with acute dyspnea or ACS; risk stratification in CHF, ACS, and PE; therapeutic monitoring; screening in the asymptomatic—BNP has wrestled with almost as many foes as Hercules, and researchers are still working on new uses for it. It will be intriguing to see how many potential applications of BNP measurement are eventually adopted.

At present, according to Dr. deLemos, the dominant indication for BNP measurement is for ruling congestive heart failure in or out in patients who come to the emergency department short of breath at rest or with marked edema. Data from the Breathing Not Properly (BNP) Multinational Study showed that BNP measurement plus clinical judgment was superior to clinical judgment alone in the emergency diagnosis of CHF (McCullough PA, et al. Circulation. 2002; 106: 416-422). In a later publication from the same group, a BNP level of >100 pg/mL was "the strongest independent predictor" of CHF in this setting, with 90 percent sensitivity and 76 percent specificity for CHF as the cause of the breathing problem (Maisel AS, et al. N Engl J Med. 2002;347: 161-167). "If BNP is very high or very low, it is diagnostically very helpful for these patients," says Dr. deLemos. A person short of breath at rest with BNP <100 has a less than five percent likelihood of having CHF as the cause. At the other extreme, in a person with known heart disease, a BNP in the 1,300 to 1,400 range would make Dr. deLemos confident that CHF is the cause of the breathing problem. "Unfortunately," he says, "many patients with cardiac disease have BNP levels in the middle, so one issue is figuring out the meaning of values in the gray zone."

Dr. Apple finesses the interpretation issue by simply reporting any result >100 as "abnormal." If he is asked for a consult, he requests the clinical context. "I can give a long list of other pathologies that can produce a rise in BNP," he says. "BNP is the HbA1C of filling pressures. Numerous pathologic mechanisms can cause myocardial stretch. That’s why the specificity of BNP for heart failure in studies is around 70 to 75 percent."

A recent randomized study from Switzerland took the work of the BNP trial group a step further: One group of ED physicians managing patients who presented with acute dyspnea were given patients’ BNP values and advised that a BNP level <100 made the diagnosis of CHF unlikely while a level >500 made it highly likely. Another group managed patients in the standard way. Providing information about BNP reduced the need for hospitalization and intensive care and decreased time to discharge in hospitalized patients, with a concomitant reduction in cost. Mortality was not altered (Mueller C, et al. N Engl J Med. 2004;350:647-654).

"This was the first randomized study on BNP testing for patient management," says Christian Mueller, MD, professor of medicine at the University Hospital, Basel, who was first author on the publication. "We were able to show that BNP testing in fact improves patient management and reduces resource utilization." Dr. Mueller emphasizes that BNP testing has been validated in the context of clearly defined clinical settings-for example, patients with acute dyspnea-and that it is not a stand-alone test. "For maximal diagnostic accuracy, BNP needs to be integrated with the clinical information available to the physician," he says.

Dr. deLemos agrees that this was an important result: "It showed that incorporating the BNP assay into the ED in a formal study design was associated with improved processes of care for acute dyspnea patients and lower cost in a real-world setting."

Use of BNP testing for evaluating and managing acute dyspnea is rapidly expanding in Europe, Dr. Mueller reports. "In Switzerland, it has become standard of care in most university hospitals," he says. "Use in doctors’ offices is also expanding, although on a much smaller scale. We are currently performing a randomized trial to specifically evaluate the use of BNP testing in the outpatient setting." In the University Hospital in Basel, BNP is also used for monitoring and risk stratification. "They have become standard of care in our institution," Dr. Mueller says.

Dr. Wang and his colleagues have made the most audacious extrapolation of BNP use: asking whether it has prognostic significance in a community-based sample (Wang TJ, et al. N Engl J Med. 2004; 350:655-663). "Ours was one of the first studies to look at the prognostic value of BNP levels in an asymptomatic population," Dr. Wang says. "Concentrations used for diagnostic purposes are in the hundreds or even thousands," he continues. "Such levels are rarely seen in the community. So one question was, are the BNP levels seen in the community—all markedly <100 pg/mL—of any importance? Are you fine if your BNP is under 100? Or does the gradient matter?"

Indeed, they found that the BNP gradient does matter: Increasing levels of BNP were associated with increased risks of death, a first cardiovascular event, heart failure, atrial fibrillation, and even stroke. Like a biochemical body scan, a single plasma BNP level above the 80th percentile󈟤 pg/mL for men and 23.3 for women, well below the CHF cutoff—identified those at increased risk for all these outcomes. (This increased risk is not explained by a small number of people with very high values: Only two percent of subjects had a BNP >80. Dr. Apple points out for clarity’s sake that "the Shionogi RIA assay used in this study doesn’t use the 100 cutoff. It is not FDA-approved and not correlated to the other BNP assays.") Only coronary heart disease events were not related to BNP. Moreover, these associations remained after adjusting for eight established risk factors.

The associations of BNP with heart failure and mortality are intuitive, Dr. Wang says. He notes that atrial fibrillation is a state that represents overload of the atrium just as heart failure represents overload of the ventricles, and that natriuretic peptides come from the atrium as well. One finding that is possibly nonintuitive is the association of BNP with stroke. "There are some cross-sectional data showing that persons with stroke have higher levels of BNP," Dr. Wang says. And mutations in genes encoding BNP are associated with stroke in both animals and humans. "So there is a small body of literature on this, which is why we looked at it. This result certainly needs to be confirmed," Dr. Wang says. Overall, he concludes, "For the most part, our findings have appealing consistency with findings in other populations."

Still, screening with BNP is not ready to be incorporated into clinical use. "Much more data are needed before we can discuss its use in the ambulatory population," Dr. Wang says. Ideally, the next steps would be confirmation of these results in other cohorts, then looking at how accurate BNP is in selecting those at risk. Another important goal is to find out what might be done to act on this information. "It is one thing to know that a blood test predicts a future event," Dr. Wang says. "We also need to know how to affect the future event, how to modify the risk."

Dr. deLemos calls this work "very intriguing."

"With a simple test they identified people who were at risk of having something bad happen to their heart many years down the line. We might imagine that someday BNP testing would be done commonly in a physician’s office as a screening tool for heart disease, just as we now order a cholesterol level or thyroid function test." He agrees that the findings need confirmation and management definition. "What we need to know," he says, "is what we do with an elevated BNP in a person who otherwise feels well."

Two laboratory issues related to BNP assays are the relative value of measuring BNP versus its inactive fragment, NT-proBNP, and criteria for selecting among the several BNP assays.

"Initially there was more research with BNP than proBNP," says Dr. deLemos. "BNP was the dominant form studied in clinical trials." Now, however, he says, "the data for proBNP are equally good. I can’t see any meaningful difference clinically between them. They both work quite well."

Dr. Apple also sees the two as clinically equivalent. "Both have strong databases," he says. "In my opinion, right now one should not be favored over the other. And you certainly don’t need to measure both."

One factor in choosing is convenience. "It is unlikely that anyone is going to get a different instrument just to run proBNP," says Tai-Po Tschang, MD, chief of pathology at St. Agnes Medical Center, Fresno, Calif. "You are going to run whatever you have an instrument to run. ProBNP is only a viable choice for laboratories who already have a Roche platform."

Another factor is clinician choice. "Clinicians seem to prefer BNP to proBNP," says Dr. Jarolim at Brigham and Women’s. "I think it is more a psychological thing. People like to measure the physiologically active compound." However, he says, "proBNP may become more important should physicians find it useful to follow the intrinsic BNP production in patients treated by synthetic BNP."

With regard to choosing a BNP assay, among those CAP TODAY interviewed for this story, almost all options were represented. "People choose on systems issues," says Dr. deLemos. "There is no reason to buy new equipment if you already have one manufacturer’s platform in your laboratory."

Dr. deLemos continues to use the Biosite Triage point-of-care instrument. "We have had great success with Biosite," he says. He has used it primarily in the central laboratory, its most common location. When Dr. deLemos used the Biosite instrument in outpatient settings, the central laboratory usually took care of maintenance and QC; sometimes nurses ran the test and took care of technical aspects. "The Triage is a flexible device that lends itself to multiple models of usage," Dr. deLemos says. "We have not had problems with QC issues." He notes that Triage is the only point-of-care device for BNP assay, which makes it suitable for physicians’ offices and specialized heart failure clinics.

Dr. Apple initially established the Biosite as a point-of-care test in an ED satellite laboratory staffed by the central laboratory. Turnaround time was 30 minutes. BNP samples from the rest of the hospital were sent by tube to the ED laboratory. Now, because of clinician preference, he is shifting troponin from the central laboratory to the ED laboratory and bringing the Triage assay into the central laboratory where it will be done on the Beckman Coulter Access. Troponin will then have a 30-minute turnaround time, while TAT for BNP will be 60 minutes. "Our ED physicians are comfortable with that because BNP is not a stand-alone test," he says. "They prefer to have a 30-minute turnaround time for troponin." He will do a small 30- to 50-patient crossover comparison to verify that automated results agree with the manual mode.

Dr. Jarolim, like Dr. deLemos, initially installed Triage meters in the central laboratory. "Our hospital has a pneumatic tube system, which makes it efficient to centralize this assay," he says. Samples from the heart failure clinic were also tested in the central laboratory. "We promised turnaround time under one hour and that is what we are getting," he says.

However, he is now planning to switch for automation reasons. "While the Biosite has performed well," he says, "obviously it is a mostly manual assay, which requires pipetting into cartridges, manual reading, and printing out. And the instrument is not interfaced to our hospital information system. So, while being perfectly happy with the performance of the assay, we would like to have something more automated with less hands-on time."

Since the laboratory has a Bayer Centaur and already does its cardiac markers on it, the Bayer assay is "a logical choice," he says. He is now analyzing thousands of specimens with the Bayer assay in a clinical trial. "So we will soon have lots of experience measuring BNP on the Centaur," he says. His contract with Biosite expires at about the same time the clinical trial ends. He will most likely switch at that time. Although Dr. Jarolim hasn’t formally compared the two assays, the Bayer assay seems to be more precise judging on the basis of preliminary data. "We would expect that based on the principles of the two assays," he says. "The Biosite test works as a lateral flow immunofluorescent assay, while Bayer is a chemiluminescent two-site sandwich immunoassay."

Doing Biosite assays in the central laboratory was also Dr. Tschang’s initial setup. "No matter how robust they claim the assay is, there are many studies showing that we do better in the central laboratory," he says. Specimens from satellite laboratories are sent by courier to the central laboratory. His turnaround time was less than one hour from receipt of the sample. As volume rose from 5,400 tests in 2002 to 7,500 in 2003, automation became more important. So Dr. Tschang adopted the Bayer assay as soon as it came out; he has been running BNP on the Centaur platform since September 2003. Dr. Tschang notes that automation offers not only walkaway performance with resultant labor savings but also a bidirectional interface. "A handheld instrument can have a result reporting interface," he says, "but not a true bidirectional interface." He retained the Biosite assay for one month and ran parallel values with the two assays on inpatients to ensure comparable serial values. Dr. Tschang found Bayer’s price an issue, but negotiated a quote "a bit lower" than Biosite’s cost. "I think we still pay too much," he says, expressing what is probably a common sentiment. As more options become available, he expects more competitive pricing.

When Dr. Tschang switched assays, he ran a parallel study and found that the Bayer assay runs lower than the Biosite. However, he did not find it necessary to change the reference range. He also found that the coefficient of variation for values at the high end of the range is significantly lower for the Bayer assay on the Centaur than for the Biosite assay. "I’m not sold that Biosite is the gold standard," he says. "When a new assay has a tighter CV and they differ, how do I know which is correct?"

Two laboratorians interviewed have switched or are preparing to switch to the Abbott assay. In the Swiss study, the Biosite assay was used, primarily because it was the only one approved at the time, says Andre Scholer, PhD, head of the clinical chemistry laboratory, Central Laboratory Department, University Hospital, Basel. "Now we use the Abbott assay on the AxSym," Dr. Scholer says. "We have too many test requests to stay with a manual, time-consuming method." Dr. Scholer formally compared the two assays and obtained "a good correlation," he says. "The regression line calculated by the Passing-Bablok method gave us the certainty to have nearly the same results, so we are not re-calibrating cutoffs." Values with the Abbott assay equalled 0.97 (Triage value) + 1.5 ng/L. [In a study by a separate group, the Passing-Bablok equation for the Bayer assay was 0.78 (Triage value) + 5.89 ng/L (Wu AH, et al. Clin Chem [serial online]. 2004 Mar 9).]

Abbott’s assay is also being evaluated at Holy Cross Medical Center in Mission Hills, Calif., says chemistry supervisor Bhanu Bawal, MS(CASCP). "We have not yet transferred from Biosite to Abbott," says Bawal. "We are looking at the data before we make that decision. And we will have to notify our medical committee." Automation is the main reason for switching, and because the laboratory already has an AxSym, the Abbott assay is the preferred alternative. Another reason, Bawal says, is that "the CV with the Biosite is much higher than what we see on the AxSym." Like Dr. Jarolim, she attributes the difference in CV to the different methods. Abbott says BNP values with its assay will be 10 to 12 percent higher than with Biosite, according to Bawal.

One advantage of switching to the Abbott assay is cost savings, Bawal says. Her laboratory performs about 400 BNPs per month. She acknowledges that Biosite provides QC simulators, which avoids the cost of controls. "But we still do run controls," she says. "Any guideline says you are supposed to run QC at the low and high end each 24 hours, so I don’t understand why people will not be running QC on a Biosite. The QC simulator tells you the machine is running OK, but you test patient specimens on real cartridges. You want to make sure those cartridges are functioning, so you still need to run controls."

Dr. Apple, who is president of the Academy of Clinical Laboratory Physicians and Scientists, points to several sets of data, both published and in press, that illuminate the use of BNP. He and Alan Wu, PhD, director of clinical chemistry and toxicology in the Department of Pathology and Laboratory Medicine at Hartford (Conn.) Hospital, surveyed use of BNP in their hospitals among 430 specimens tested between August 2001 and April 2002, right after the assay was introduced. In addition to verifying BNP’s "high sensitivity and excellent negative predictive value" for congestive heart failure, they found that 44 percent of samples came from the ED and 45 percent from cardiology (Apple FS, et al. Clin Chim Acta. 2003;328:191-193). In a repeat survey taken in early 2004, they documented a shift. The number of total tests ordered increased, while the number ordered from the ED remained stable. Thus, the ED accounted for only about 20 percent of orders, while about 65 percent were done in cardiology areas for monitoring patients. "From talking to my clinical colleagues," Dr. Apple says, "this trend probably reflects overutilization, in my opinion."

Two studies dealing with biological variation reinforce this conclusion. Dr. Wu showed that anything less than about a twofold change in BNP or NT-proBNP is not outside biological variation (Wu AH, et al. Am J Cardiol. 2003;92: 628-631). "So a drop from, say, 600 to 500 is not meaningful," Dr. Apple says. In a paper that is in press, Drs. Wu and Apple monitored patients who had two draws at separate time points. "It took five to seven days for 50 percent of those patients to change outside the range of biological variation, a 100 percent change," Dr. Apple reports. This shows that frequent monitoring of inpatients may not be warranted or helpful. Nonetheless, Dr. Apple finds, house staff often order tests close together. "They may order a BNP on day two and/or day three," he says. "They are treating the number, not the patient." He strongly advocates getting only one followup value 24 hours pre-discharge to make sure therapy has been successful.

"BNP is a great test," Dr. Apple agrees, even a "blockbuster." But it needs to be used more critically. In 1999 the National Academy of Clinical Biochemistry’s Clinical Chemistry Committee published standards for use of cardiac markers (Clin Chem. 1999;45:1104-1121). The committee has been meeting again for the last year to revise those guidelines, with about half of the effort going to troponin and half to BNP in heart failure. Recommendations will cover both analytical issues and clinical use. "This committee is a who’s who of cardiologists and laboratory people," Dr. Apple says. "Our concept is to have the same guideline messages coming from laboratory and cardiac groups."

The Arnold O. Beckman conference in Boston in May will be devoted to the new guidelines, which will be posted for review on the Web site of the American Association for Clinical Chemistry before and after the conference, then written up and published. "I think it is safe to say that the guidelines will reflect the caution that this test should not be overused," Dr. Apple says. "It is not a stand-alone test; you have to put it into an appropriate clinical context."

It is also important to distinguish between proven applications and those for which there is now more enthusiasm than proof.

"I am not sure if all these studies will pan out as useful applications of BNP," says Dr. Jarolim. "Certainly the ideas sound right. But it remains to be seen whether BNP will be as useful as one might expect."

William Check is a medical writer in Wilmette, Ill.