CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
In a study that examined the national prevalence of subclinical CVD—assessed by elevated NT-proBNP or cardiac troponin and using stored serum samples—in 10,304 U.S. adults without a history of CVD, Fang, et al., found that in patients with diabetes, the risk of mortality was highest when both markers were simultaneously elevated (Fang M, et al. J Am Heart Assoc. 2023;12[11]:e029083). The authors looked at cardiovascular disease, Dr. Jarolim notes, rather than incident heart failure, and they used the cutoffs recommended in the ADA report (NT-proBNP ≥125 pg/mL and high-sensitivity cardiac troponin T ≥14 ng/L, which is the 99th percentile used in Europe). They found that the crude prevalence of subclinical CVD was about twice as high in adults with diabetes versus those without. About one in three adults with diabetes had subclinical CVD: hs-cTnT was elevated in 19 percent, NT-proBNP was elevated in 23 percent, and both biomarkers were elevated in nine percent. Among adults with diabetes, the cumulative incidence of all-cause and CVD mortality was substantially higher in those with elevated high-sensitivity cardiac troponin T or NT-proBNP.
For high-sensitivity cardiac troponin assays, “we don’t have a gold standard that would allow us to say this amount or standard should be detected,” Dr. Jarolim says, “so we use the 99th percentile.” When it comes to the high-sensitivity cardiac troponin T assay, the FDA in 2017 approved cutoffs of 14 ng/L in women and 22 ng/L in men. “At Mass General Brigham we decided to be more conservative,” he says. “We’re using 10 nanograms per liter for women and 15 nanograms per liter for men for the diagnosis of acute myocardial infarction.” But some situations call for a more lenient approach, he says. At Dana-Farber, where cardiac troponin is used to monitor patients on immune checkpoint inhibitors, the FDA-approved cutoffs are used. “It would be too restrictive to use the low cutoffs we use for MI [at Brigham],” he says. “It would exclude half the patients from cancer trials, which are potentially lifesaving.”
For patients with type 2 diabetes, there’s evidence to support the more cautious approach. Pandey, et al., he notes, use the FDA-approved troponin T assay’s limit of quantitation of ≥ 6 ng/L in their biomarker-based risk score to identify individuals with dysglycemia who are at a five-year risk for incident heart failure (Pandey A, et al. JACC Heart Fail. 2021;9[3]:215–223). As a marker of long-term risk, Dr. Jarolim says, “it makes sense to go lower than the 99th percentile.”
Grinstein, et al., found in their study of 4,160 patients with acute coronary syndrome that those with baseline high-sensitivity cardiac troponin T of 14 ng/L or more had a higher 30-day risk of cardiovascular death or myocardial infarction than those below 14 ng/L (9.1 percent versus 1.9 percent). But even patients who had levels between 14 ng/L and the limit of detection of 3 ng/L used in Europe—that is, within the reference range—had a two percent risk. Patients with undetectable troponin had zero percent risk (Grinstein J, et al. Clin Cardiol. 2015;38[4]:230–235).
Cavender, et al., studied the incidence of cardiovascular disease or hospitalization for heart failure in 3,808 patients with type 2 diabetes using a high-sensitivity cardiac troponin assay. They found that patients who had troponin I levels greater than 26 ng/L after six months had a two-year incidence of 17.5 percent. But patients who measured between 10 and 26 ng/L after six months had almost the same two-year incidence, at 15.1 percent (Cavender MA, et al. Circulation. 2017;135[20]:1911–1921). “So it isn’t enough to be in the so-called reference range,” Dr. Jarolim says. “You need to be lower.”
A large study of the general population, which proposed specific high-sensitivity cardiac troponin I cutoffs for cardiovascular risk stratification in asymptomatic patients, found that “levels greater than 12 [ng/L] for men and greater than 10 [ng/L] for women are associated with significant elevated long-term risk of adverse outcomes,” Dr. Jarolim says (Blankenberg S, et al. Eur Heart J. 2016;37[30]:2428–2437). “So again, you want to be in the low single digits.”
Whether C-reactive protein, too, could improve clinical risk scores has come up. “Brigham and Women’s Hospital advocated the use of high-sensitivity CRP as a cardiac risk factor, based on several studies,” he says. “But many follow-up studies, including some by our group, have shown that its predictive value is lower than that of the natriuretic peptide or high-sensitivity cardiac troponin assays. It’s also a finicky marker, in that it responds to any inflammation you might have. So I don’t think CRP would add much.”
Dr. Jarolim doesn’t expect the biomarker testing to have an outsize effect on laboratory operations, even after more institutions begin to follow the ADA recommendation.
Test volumes will increase, “but it won’t happen overnight,” he says. “And compared to the clinical chemistry lab at Brigham, where we run eight million tests per year, this will be thousands or tens of thousands of tests, added gradually. So that’s a relatively minor impact.”
And because the testing will be performed in the outpatient setting, “turnaround time is not a critical issue,” he says, and “theoretically it should be reimbursed, especially if payers appreciate that this approach should postpone or even prevent the onset of heart failure.” Still, he adds, “Screening is a dirty word in the reimbursement world.”
At Brigham, troponin orders in the outpatient setting for symptomatic patients are discouraged, he says. The lab runs 150 cardiac troponin tests daily, of which about two-thirds are elevated, and it isn’t possible to notify every clinician whose patient has an abnormal result. “So we ask clinicians to send symptomatic patients to the emergency department. But if cardiac troponin becomes a standard risk prediction test, we will need to change this approach.”
The need for new diagnostic cutoffs and age- and sex-specific ranges and BMI adjustments may mean that “our resulting screens get a little more complex,” Dr. Jarolim says. One solution would be to create a new test in the laboratory information system—cardiac troponin as a risk predictor, for example, with a different cutoff. There’s precedent for it, he says. “For C-reactive protein, we use the same assay as two different markers—inflammation marker versus cardiac risk factor.” For cardiac risk prediction the cutoff is 3 mg/L, and for inflammation it’s 10 mg/L. The two tests use the same reagent but have different order and charge codes. “So it wouldn’t be unheard of.”
Implementing the biomarker testing in clinical practice won’t be easy, he concedes. “An overwhelmed primary care physician may have a problem ordering NT-proBNP. It’s not an inexpensive assay.” Internist Jennifer Zreloff, MD, of Emory University, a co-presenter in the ADLM session, says that it wouldn’t be difficult to add to the checklist another laboratory test. “But it hasn’t gotten to our radar yet. We’re focusing already on a lot of cardiovascular issues. If we can’t get the blood pressure of our patients controlled, if we can’t convince them to take a statin . . . where is screening for the early stages of heart failure on that to-do list?”
In some countries, Dr. Jarolim notes, the natriuretic peptides are not part of the diagnostic toolkit. “Many hospitals in Spain, for instance, use CA-125, the ovarian cancer marker, as a marker of congestion for monitoring heart failure. And we see patients previously treated for ovarian cancer who don’t have a relapse, yet their CA-125 is increasing.” A physician may incorrectly conclude a patient has a cancer relapse when they’re exhibiting signs of heart failure. “So it’s difficult to implement these tests in primary care,” he says.
As Mass General Brigham undergoes consolidation and a transition to Epic Beaker, a push for standardization across the hospital system is being made. But the cardiac troponin reference ranges at Dana-Farber will remain distinct from those at Brigham, Dr. Jarolim says. “It would be counterproductive to use the low cutoffs. And it may be reasonable to use these higher cutoffs for monitoring cancer patients on potentially cardiotoxic therapies in other institutions, including Mass General Brigham.”
With high-sensitivity cardiac troponin becoming more established in clinical practice, Dr. Jarolim envisions different cutoffs for various indications—a specific cutoff for monitoring cardiovascular safety of potential cardiotoxic therapies, for example, or for myocardial injury during noncardiac surgery. The latter in particular is needed, he says, because troponin elevations often occur in surgery, with some patients developing myocardial injury. “Among other factors, it’s underdiagnosed because of the use of anesthesia. Patients have an MI and don’t know it. So again, in this case, a different cutoff may be warranted.”
In summing up, Dr. Jarolim said the “jury is out” on whether a single marker or risk scores should be used. “I would say one [biomarker] for now,” he says. Whether that’s NT-proBNP, BNP, or high-sensitivity cardiac troponin is unknown, as are the optimal cutoffs.
“However, we know that NT-proBNP and troponin go up with age significantly, and we know that women have less troponin but more NT-proBNP and BNP than men.” That and having to adjust for BMI point to perhaps using troponin with the natriuretic peptides in some situations.
“We can create even larger risk scores” with additional markers, “which may have slightly better C-statistics, but I don’t think that’s a viable approach,” he says.
Charna Albert is CAP TODAY associate contributing editor.