Value of Natriuretic Peptide Measurements in HFpEF

By Michael H. Crawford, MD, Editor

Synopsis: A pooled analysis of four trials of drug therapy for heart failure with preserved ejection fraction (HFpEF) patients has shown that, although the risk of adverse outcomes is higher with increasing baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, the effect is attenuated at higher body mass index levels, such that lower NT-proBNP cutoffs for risk-stratifying obese patients need to be developed.

Source: Ostrominski JW, Neuen BL, Claggett BL, et al. Natriuretic peptides, body mass index, and clinical outcomes in heart failure with mildly reduced or preserved ejection fraction. J Am Coll Cardiol. 2025;86(20):1823-1839.

Smaller studies of patients with heart failure with preserved ejection fraction (HFpEF) have shown problems with interpreting natriuretic peptides in obese patients because they tend to be lower than in non-obese subjects. To help clarify this issue, investigators from four large, randomized trials of drug therapy for patients with HFpEF pooled all the trial data to evaluate the relationship among baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP), body mass index (BMI), and clinical outcomes.

The trials and the drugs tested were I-PRESERVE (irbesartan vs. placebo), TOPCAT (spironolactone vs. placebo), PARAGON-HF (angiotensin receptor-neprilysin inhibitor vs. valsartan), and DELIVER (dapagliflozin vs. placebo). The present analysis included all patients with a BMI > 18.5 kg/m² and NT-proBNP data. This resulted in 14,750 patients (mean age 72 years, 50% women). Their mean BMI was 30 kg/m² (range 18.5-69.6) and the median NT-proBNP was 835 pg/mL (range 423-1,557). A history of atrial fibrillation (AF) was found in 48%. The primary outcome was cardiovascular (CV) mortality or heart failure hospitalization (HFH). Baseline BMI was stratified as follows: 18.5 kg/m² to < 25 kg/m², 25 kg/m² to < 30 kg/m², 30 kg/m² to < 35 kg/m², 35 kg/m² to < 40 kg/m², and ≥ 40 kg/m². A higher BMI was non-linearly associated with a lower NT-proBNP.

After a median follow-up of 2.8 years, a doubling of NT-proBNP was associated with a 40% higher incidence of the primary outcome (hazard ratio [HR], 1.4; 95% confidence interval [CI], 1.36-1.43, P < 0.001), but this association was blunted as BMI increased (P for the interaction = 0.008). At the same risk of the primary outcome (five events/100 person-years), NT-proBNP levels in those without AF were three-fold lower in those with a BMI ≥ 35 kg/m² (158 pg/mL) compared to those with a BMI < 35 kg/m² (450 pg/mL). On the other hand, the risk of the primary outcome ranged from 3.5 events/100 person-years in those with BMI < 30 kg/m² to 7.3 events/100 person-years in those with BMI ≥ 40 kg/m².

The authors concluded that NT-proBNP substantially underestimates the absolute risk of HF outcomes among those with higher BMI. This suggests that lower NT-proBNP thresholds should be developed for the risk stratification of HF therapy intensity in HFpEF patients with high BMIs.

Commentary

Obesity is a risk factor for HFpEF and is present in the majority of such patients. Guidelines recommend using natriuretic peptide (NP) measurements for the diagnosis and management of heart failure patients, but applying this metric to obese heart failure patients is problematic because of the relatively lower NP values in obese patients. Why this occurs is unclear, but it is known that NP clearance is associated with lean mass, not fat mass. Thus, NPs are reduced in those with sarcopenia and frailty, which are common in obese patients. Alternatively, when BMI is > 30, pericardial restraint may reduce NP secretion by the heart.

The American Diabetes Association recommends an NT-proBNP level of ≥ 125 pg/mL for HF screening and intensifying therapy for those with known HF, without considering BMI. As the pooled trials study shows, many with HFpEF and BMI ≥ 35 kg/m² may be below this threshold. Thus, it has been suggested that NT-proBNP cutoff levels should be tailored to obese patients. What has been proposed is that for patients with a BMI < 35 kg/m², NT-proBNP ≥ 500 pg/mL be used and for patients with a BMI > 35 kg/m², NT-proBNP ≥ 200 pg/mL be used. Using these cutoffs in the pooled data would result in equivalent outcomes for these two groups. Also, other factors besides NPs could be used, such as left ventricular filling pressure estimates.

There are limitations to this pooled analysis to consider. Two of the trials excluded patients with very high BMIs (e.g., > 50 kg/m²). Also, some used NP minimum levels for entry, which could have excluded some patients with a very high BMI. Other covariates not considered may affect NP levels or outcomes and induce residual confounding. For example, AF, diabetes, and hypertension are known to increase NPs. About half of each BMI patient strata had a history of AF, about 40% had diabetes, and about 90% had hypertension, so these diseases may have affected the BMI strata comparison results. Only BMI was used to define obesity and no other adiposity-related anthropometrics. The application of these findings to patients with advanced renal disease is unknown since such patients were excluded. Finally, the population of the pooled analysis was largely white, so the results may not apply to other races or ethnicities. Despite these and other limitations of this study, it seems clear that NP levels need to be considered in the context of BMI.

Michael H. Crawford, MD, is Professor Emeritus of Medicine and Consulting Cardiologist, UCSF Health, San Francisco.