CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Charna Albert
March 2024—For patients with type 2 diabetes, the cardiac biomarkers are a better predictor of early-stage heart failure than conventional risk prediction scores. “We need to use biomarkers,” says Petr Jarolim, MD, PhD, medical director of clinical chemistry, Brigham and Women’s Hospital, and medical director of clinical laboratories, Dana-Farber Cancer Institute.
The supporting evidence is clear: In a session at the ADLM meeting last year, Dr. Jarolim, who is also director of the hospital’s biomarker research and clinical trials laboratory and professor of pathology at Harvard Medical School, pointed to a study that found that NT-proBNP was the strongest independent predictor of future cardiovascular events in patients with type 2 diabetes, outperforming echocardiography, albuminuria, and electrocardiography (Busch N, et al. J Diabetes. 2021;13[9]:754–763). And the expert consensus concurs. In a 2022 report, the American Diabetes Association and American College of Cardiology recommended a natriuretic peptide or high-sensitivity cardiac troponin measurement at least yearly in patients with type 2 diabetes (Pop-Busui R, et al. Diabetes Care. 2022;45[7]:1670–1690).
But practically speaking, there are details to be ironed out, starting with the proposed biomarker thresholds, says Dr. Jarolim, who discussed the report in his ADLM presentation and in a recent interview with CAP TODAY. “The recommendations are important,” he says. “But I can’t completely agree with the cutoffs proposed in the recommendations.”
Those cutoffs are 50 pg/mL for BNP, 125 pg/mL for NT-proBNP, and a value greater than the 99th percentile for a healthy patient population for high-sensitivity cardiac troponin. For NT-proBNP, Dr. Jarolim says, “125 is a fairly low reading. It is predictive, and if you go even lower you identify more patients and may be able to identify them earlier, at the expense of a further decrease in specificity. But it would be important to optimize it.”
Dr. Jarolim
Women, he says, have roughly twice the levels of natriuretic peptides as men of the same age group, and concentrations increase with age in both sexes. “So, all that suggests that it should be more granular and more specific. And it should be able to predict the early onset of heart failure with higher certainty.”
“It’s a simplistic solution, at this point, to use this cutoff,” he adds.
The first study to propose the 125 pg/mL cutoff had “surprisingly limited data,” he says, with a population of 631 patients with diabetes and a one-year follow-up (Huelsmann M, et al. Eur Heart J. 2008; 29[18]:2259–2264). At 125 pg/mL, the NT-proBNP assay had a sensitivity of 0.795 and a negative predictive value of 97.6 percent for hospitalization or death within the observation period. “The assay has high sensitivity and high negative predictive value,” Dr. Jarolim says. “You can’t argue with that. The lower you go, the higher the sensitivity—that’s how our testing works.” The positive predictive value was 12.9 percent. “But if you look at real numbers, or the real prevalence, that’s an overestimate,” he says. “If it were a tumor marker you probably wouldn’t use it for screening with a positive predictive value of 13 percent. Yet based on this paper, numerous studies have published that NT-proBNP of greater than 125 is associated with higher risk of progression to heart failure, seemingly suggesting that this is the optimal cutoff.”
Some experts admit that a positive predictive value of 13 percent isn’t optimal, he says, but they don’t see it as a critical issue because “by the time we get optimal cutoffs for positive predictive value, we are in a zone that includes people with already established heart failure, and the goal of this approach is to aim for people in transition.”
But the low positive predictive value could result in overdiagnosis or overtreatment with sodium-glucose cotransporter-2 inhibitors, he says. “And it’s not an inexpensive therapy.”
Some laboratories, such as Mayo Clinic, use age- and sex-stratified reference ranges for NT-proBNP. At Mayo Clinic, he says, the lowest upper reference limit for women is still above 125 pg/mL. “The lowest is in the 45- to 54-year-old group, and it’s 141.” For women 65 and older it’s less than 540 pg/mL. “And these are all apparently healthy women.”
In contrast, the package insert for one NT-proBNP assay puts the cutoff at 125 pg/mL for patients under 75, and 450 pg/mL for patients over 75. “Here, if you have 250 and you are 74 years old, you are at risk of heart failure and should be treated. If you have 250 and you are 76 years old, you are well within the reference range. So we need to look carefully at these cutoffs.”
“That said, we know that BNP and NT-proBNP perform better than established diabetes markers,” he says. Zelniker, et al., showed that patients with higher NT-proBNP quartiles had increased rates of cardiovascular death and hospitalization for heart failure (13.7 percent [Q4, >165 pg/mL] versus 1.0 percent [Q1, ≤35 pg/mL]) (Zelniker TA, et al. Eur J Heart Fail. 2021; 23[6]:1026–1036). They also found that the incidence of cardiovascular death and hospitalization in patients without a history of heart failure but with biomarker levels of 450 pg/mL or higher was similar to the incidence in the overall subgroup of patients with a history of heart failure—18.3 percent versus 19.9 percent.
As a measure of risk for heart failure, the difference between BNP and NT-proBNP is negligible, Dr. Jarolim says. NT-proBNP is approved for multiple sample types, unlike BNP, which is approved for EDTA plasma only. “NT-proBNP also is slightly more sensitive because it’s more stable and therefore has a longer half-life and circulates in higher concentrations,” he says. “But as far as predictive value goes, they are comparable.”
Dr. Jarolim and others studied serial NT-proBNP monitoring in a study of 5,380 patients with type 2 diabetes (Jarolim P, et al. Diabetes Care. 2018;41[7]:1510–1515). Outcomes were stratified by change in NT-proBNP between the baseline measurement and six months. “We divided patients into two categories: high, when the NT-proBNP was greater than 400 [pg/mL], and low, when NT-proBNP levels were less than 400,” he says. Patients who had persistently high NT-proBNP or developed high NT-proBNP at six months were at significantly higher risk for cardiovascular death or heart failure than those in whom NT-proBNP remained low at both time points or who had a high NT-proBNP baseline measurement that subsequently declined to the low category. “Their outcomes are almost the same as those who started low and continued low,” he says. “So it is worth doing these repeat measurements” and attempting to lower NT-proBNP levels through therapy.
Body mass index affects the natriuretic peptides. “It’s known that levels are lower in patients with higher BMI, so this affects the cutoff,” Dr. Jarolim says. “Initially we thought this was because adipose tissue has receptors for BNP, so it would make sense that in overweight people BNP would be lower.” But NT-proBNP levels also are lower in those with higher BMI, he says. “So that suggests that obese people produce fewer natriuretic peptides.” The Heart Failure Association of the European Society of Cardiology recommends cutoff concentrations 50 percent lower in obese patients in its practical guidance on the use of natriuretic peptides (Mueller C, et al. Eur J Heart Fail. 2019;21[6]:715–731).
Dr. Jarolim and others investigated the interaction between NT-proBNP and body mass index and its effects on heart failure risk in a study of 24,455 overweight or obese patients (Patel SM, et al. Eur J Heart Fail. Published online Dec. 22, 2023. doi:10.1002/ejhf.3118). They found a significant inverse association between NT-proBNP and BMI that persisted after adjustment for all clinical variables. Higher NT-proBNP and higher BMI were each associated with greater probability of hospitalization for heart failure. In patients with an NT-proBNP of less than 125 pg/mL, risk of hospitalization was low irrespective of BMI. But in those with an NT-proBNP of more than 125 pg/mL, risk of hospitalization for any given NT-proBNP value was significantly higher among those with obesity. In particular, the authors write, clinicians should recognize the meaningful risk of hospitalization for heart failure in patients with severe obesity with low-level elevations in NT-proBNP between 125 and 450 pg/mL.
“So we definitely should adjust for BMI,” Dr. Jarolim says.
In the emergency setting, if a patient has shortness of breath with or without chest pain, congestion, and other symptoms, a natriuretic peptide test is the test to order, Dr. Jarolim says.
“The natriuretic peptides are a prototypical marker of heart failure.” Cardiac troponin is a more generic marker of myocardial damage that can signify a number of conditions. But elevated cardiac troponin is associated with the onset of heart failure, he says. In his own research, he’s demonstrated that troponin levels increase significantly with the increasing severity of heart failure (Jarolim P, et al. Clin Chem. 2015;61[10]:1283–1291). “So clearly troponin is associated with heart failure and has solid predictive value.” Using both markers in tandem may be an asset in some scenarios, he says. In patients with higher BMI, for example, “troponin as an adjunct to the natriuretic peptides may be helpful.”