By Van Selby, MD

Assistant Professor of Medicine, University of California, San Francisco Cardiology Division, Advanced Heart Failure Section

Dr. Selby reports no financial relationships relevant to this field of study.

SYNOPSIS: In patients presenting to the ED with acute dyspnea, age-based NT-proBNP cutpoints help diagnose acute heart failure.

SOURCE: Januzzi JL, Chen-Tournoux AA, Christenson RH, et al. N-terminal pro-b-type natriuretic peptide in the emergency department: The ICON RELOADED study. J Am Coll Cardiol 2018;71:1191-1200.

Natriuretic peptides, including N-terminal prohormone of brain natriuretic peptide (NT-proBNP), are used commonly in the evaluation of acute dyspnea and receive a strong class Ia recommendation in clinical practice guidelines. However, there is not universal agreement regarding the appropriate cutoff values for identifying acute heart failure (HF). The authors of previous studies have proposed specific cutoffs based on the patient’s age. To evaluate whether these criteria are still valid in contemporary practice, patients presenting to 19 EDs in North America for dyspnea underwent blood draws for measurement of serum NT-proBNP. A clinical events committee that was blinded to the NT-proBNP level independently reviewed each case to determine whether the patient had acute HF. The authors evaluated the ability of NT-proBNP to diagnose HF, using a cutoff of > 450 pg/mL in patients < 50 years of age, > 900 pg/mL in patients aged 50-75 years, and > 1,800 pg/mL in patients > 75 years of age. Of 1,461 patients enrolled, 277 were diagnosed with HF. The average age of all patients was 56 years, and half were female. NT-proBNP levels predicted acute HF in the overall study population, with an area under the receiver operating curve of 0.9 (P < 0.001, with 1.0 representing a perfect test). Using the age-specific cutoffs of 450 pg/mL, 900 pg/mL, and 1,800 pg/mL to diagnose acute HF yielded sensitivities of 85.7%, 79.3%, and 75.9% in their respective age groups. Specificity also was strong at 93.9%, 84.0%, and 75.0%. An NT-proBNP level < 300 pg/mL was very useful for ruling out HF in all age groups, with a sensitivity of 93.9% and specificity of 98.0%. The authors concluded that in patients presenting to the ED with dyspnea, age-based NT-proBNP cutoffs aid in the diagnosis of acute HF, and a value < 300 pg/mL strongly rules out acute HF in all age groups.

COMMENTARY

Recommended cutoff values for the diagnosis of acute HF using NT-proBNP vary substantially. NT-proBNP is renally cleared; therefore, serum levels are affected by age-related declines in renal function. The authors of previous studies found that using age-based NT-proBNP cutoffs improved the accuracy of NT-proBNP for diagnosing acute HF. Since the publication of these studies, there has been significant change in both the demographics and treatment of HF. Here, in a large prospective cohort, Januzzi et al showed that age-based NT-proBNP cutpoints remain useful for the diagnosis of acute HF and improve diagnostic accuracy compared to any single age-independent cutoff. NT-proBNP is particularly useful for “ruling in” HF among patients < 50 years of age. Among these patients, an NT-proBNP level > 450 pg/mL predicts a diagnosis of acute HF with an impressive specificity of 93.9% and a positive likelihood ratio of 14.08. NT-proBNP also was excellent at ruling out HF when the level was < 300 pg/mL, a useful tool when evaluating patients for causes of acute dyspnea. Unfortunately, this study cannot solve a well-known limitation of both NT-proBNP and BNP: the “gray zone” of values that can neither rule in or out a diagnosis of HF. Using the cutoffs recommended in this study, the gray zone varies from 300-450 pg/mL in patients < 50 years of age to 300-1,800 pg/mL in patients > 75 years of age. In these cases, other diagnostic tools must be used to diagnose or exclude acute HF.

It is important to keep in mind the clinical context when interpreting an NT-proBNP level. Januzzi et al performed their study in patients presenting to the ED with acute dyspnea. The cutpoints identified are different from what should be used in other settings. For example, the FDA recommends much lower NT-proBNP cutoff values of 125 pg/mL and 450 pg/mL for patients < 75 years of age and ≥ 75 years of age, respectively. These values were developed for identifying chronic HF in stable outpatients. Applying the FDA criteria to an ED setting would lead to significant misdiagnosis of acute HF. Similarly, applying the cutoffs from the Januzzi et al study to an outpatient setting would lead to missed diagnoses of chronic HF. Natriuretic peptides, including NT-proBNP, remain an easy, useful aid for the diagnosis of acute HF in patients presenting with dyspnea. To use them appropriately, it is imperative to set clear cutoffs. Januzzi et al have shown that an age-stratified set of NT-proBNP cutoffs can identify acute HF in patients presenting to the ED with dyspnea.