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Cardiac biomarkers: easy to use and misuse
By Stacey Butterfield
“It's easy to measure biomarkers,” cardiologist James Januzzi Jr., MD, told attendees at the American College of Cardiology's annual meeting, held in Chicago in March.
But correctly interpreting and acting on the biomarkers can be far more complicated, according to Dr. Januzzi and other experts who spoke at the meeting. They offered some advice on using cardiac troponin and natriuretic peptide measurements to optimize the care of patients.
Measuring biomarkers is easy; correctly interpreting and acting on them can be far more complicated. Photo by Thinkstock.
“Natriuretic peptides wear the crown as the gold standard biomarker for predicting adverse outcomes in patients” with heart failure, said Dr. Januzzi, who is an associate professor of medicine at Harvard University. However, even the royalty of biomarkers can be overused and misinterpreted, he added.
One common misunderstanding about both natriuretic peptides and troponin is that elevations in these biomarkers are definitive indicators of specific diagnoses—heart failure and myocardial infarction, respectively.
One common misunderstanding about both natriuretic peptides and troponin is that elevations in these biomarkers are definitive indicators of specific diagnoses.
“People have written on and on about how [natriuretic peptides] are biomarkers of heart failure. That's the wrong way to think about it. They are biomarkers of cardiovascular distress,” said Dr. Januzzi. Peptides can be very elevated in patients with atrial fibrillation, sepsis or burns, for example. “These patients have cardiac abnormalities, but it's not the clinical syndrome of heart failure,” he said.
The same is true of troponin, according to Allan S. Jaffe, MD, a cardiologist and professor of medicine at the Mayo Clinic in Rochester, Minn. “Be open to alternative diagnoses. We used to be in cardiology so fixated on coronary arteries that if we took a patient who had an elevated troponin to the cath lab and the angiogram [was] normal, we said, ‘All right, the troponin has to be wrong,’” he said.
However, carbon monoxide poisoning can elevate troponin, as can myocarditis. “You know that critically ill patients can have elevated troponins and there are a large number of diagnoses that go into the possible etiologies,” said Dr. Jaffe.
Other reasons for fluctuation
A number of other factors can also affect levels of these markers. “If you want a high [B-natriuretic peptide] value, get it drawn in the afternoon. If you want a low value, get it drawn in the morning,” said Dr. Jaffe. “These are the sorts of things that we as clinicians were never informed about with enough detail.”
Troponin also fluctuates, even in healthy people, but over a narrower range, and both markers vary by gender. Older patients have higher B-natriuretic peptide (BNP) levels and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and obese people have lower ones. “If you don't take this into account clinically, with the very obese patient, you're going to end up being surprised at the low numbers and make a missed diagnosis,” said Dr. Jaffe.
Variations in the assays used to measure these biomarkers can also confuse diagnosis, the experts said. “No two [troponin] assays use the same antibody configuration,” said Fred S. Apple, PhD, medical director of clinical laboratories at Hennepin County Medical Center and professor of laboratory medicine and pathology at the University of Minnesota in Minneapolis. “Beware and understand the assay you're looking at.”
Assays for NT-proBNP have slightly more consistency, but BNP assays definitely vary, Dr. Jaffe said. “You need to know, just like with troponin, what your local assay is telling you.”
Dr. Januzzi agreed. “If you have referrers that use different assays than you do, then this really becomes problematic,” he said.
Another potential problem with natriuretic peptide measurement is kidney disease, although it might not be as big an issue as some clinicians have believed. “People hold on to this misconception that NT-proBNP is entirely dependent on renal clearance. That is in fact not true,” said Dr. Januzzi. “Clearance of both [BNP and NT-proBNP] should not be affected by glomerular filtration rate until down to less than 30, and they are equally cleared by the kidneys, something people still don't realize.”
He added, “It's important to realize, however, that the prevalent structural heart disease and volume overload in patients with impaired kidney function may lead to unexpectedly high levels of BNP or NT-proBNP, which should be viewed as a true positive, given the markedly adverse prognosis associated with their elevation.”
For patients without kidney disease, a BNP of 100 pg/mL and a NT-proBNP of 900 pg/mL are reasonable cutpoints, Dr. Januzzi said, although he warned that the specificity at these numbers is not perfect for identifying a heart failure exacerbation.
“With either of these cutpoints, there's a substantial number of patients above that threshold who do not have acutely decompensated heart failure, while there are some below it that do,” he said. “If you want to maximize your negative predictive value, to exclude heart failure, one needs to use very low thresholds for either peptide. For BNP it's around 20 or 30. For NT-proBNP, it's around 300.”
“On the other hand, to improve specificity to diagnose heart failure, it's important to consider the factors that elevate BNP or NT-proBNP in those without the diagnosis,” he added. Because age significantly can affect peptide results, he recommends using age-stratified cutpoints. While a specific strategy is not well established for BNP, with NT-proBNP, using 450 pg/mL under age 50, 900 pg/mL from 50 to 75 years, and 1800 pg/mL over 75 is superior to a single cut-off. “This by no means indicates that NT-proBNP is more affected by age, only that the approach has been better validated with NT-proBNP at this point,” said Dr. Januzzi.
Managing the gray zone
Even with these guidelines, some patients will fall into a gray zone of uncertainty, he noted. “In order to get through a gray zone situation, one needs to be a good clinician and keep in mind that history and physical are still, bar none, the most important way to evaluate our patients.”
For troponin, the appropriate cutoff (when diagnosing a myocardial infarction) should be the 99th percentile value, according to Dr. Jaffe. It identifies more patients than the 10% CV value, which had previously been favored by some. “Clinicians have often advocated for using higher cutoffs because it reduces the number of elevations they have to explain,” he said. “It's taken us years to really migrate to the appropriate cutoff—the 99th percentile.”
In addition to choosing the right cutpoint, physicians also need to pay sufficient attention to trends in patients' biomarkers. “There's a tremendous need to follow and look at changes,” said Dr. Jaffe. “Look for a changing pattern when these patients present with acute coronary syndrome.”
Likewise, with BNP, the delta in an individual patient has proven to be important. “One question that's been asked is, ‘Should we be shooting for a change or should we be shooting for an absolutely lower concentration?’ It turns out both are independently important,” said Dr. Januzzi. “At the end of hospitalization, those that have a substantial reduction [from admission] have better outcomes than those that do not. However, lower is always better.”
This finding gets at another of the hot topics in natriuretic peptide measurement: whether the biomarkers should be used in treatment as well as diagnosis. “In other words, you're seeing a patient in the hospital for acute heart failure, they seem to be recompensated and yet, their natriuretic peptide values have not fallen. Should you intensify this patient's heart failure management in order to reduce natriuretic peptides?” asked Dr. Januzzi.
There's little evidence to answer this question in the hospital, he said, but some support for using BNP and NT-proBNP levels to guide treatment in the outpatient setting. Of course, ideally, all heart failure patients should be receiving medical therapy according to guideline standards, but that doesn't always happen.
“The reality is there are huge gaps in adherence to guideline-defined therapies for these patients, and natriuretic peptides may proactively identify those patients who have those gaps,” Dr. Januzzi said. Unexpectedly high peptide levels can also identify patients who aren't adhering to medication or diet and lifestyle recommendations.
“Above and beyond all that, you have to accept that a patient with an elevated natriuretic peptide is at higher risk and hence, consider reviewing their medication program for opportunities to uptitrate,” he said.
Physicians should also be thinking more about the long-term risks associated with elevated troponin, Dr. Jaffe said. The biomarker (either cardiac troponin I or T) can be an important predictor for patients without acute coronary syndrome, such as critically ill and postsurgical patients. “After these patients are discharged, often the elevated troponin is out of sight and out of mind,” he said. “Even if we don't know exactly how to treat it acutely, if you look long-term, the greater the troponin, the greater the risk.”
Follow-up for a patient with elevated troponin should at least include the basics of cardiovascular prevention, such as screening for and treating hypertension and hyperlipidemia, Dr. Jaffe added.
Troponin may play an even greater role in outpatient care once high-sensitivity assays become available, according to Dr. Apple. As of yet, no high-sensitivity assays have been cleared by the FDA, but Europe has one for troponin T on the market.
“A high-sensitivity assay should be able to measure at least 50% or 75% of the normal patients in a population, so you can follow changes from presentation to ongoing development,” he said.
These new assays might turn out to be useful in primary prevention for identifying at-risk patients and are also expected to shorten the time required to diagnose myocardial infarction. “In the contemporary assays, we looked at that six-hour window, but with the new high-sensitivity assays, we're going to be narrowing it down to a two- to three-hour window,” Dr. Apple said.
Although it's not yet certain when the high-sensitivity assays will be available in the U.S., physicians may want to start talking to their laboratories about them anyway. “It's not too early now to roll out the education process, especially within cardiology, so when the assays do get FDA-cleared, you can hit the ground running,” concluded Dr. Apple.
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