Natriuretic Peptides, Body Mass Index, and Clinical Outcomes in Heart Failure With Mildly Reduced or Preserved Ejection Fraction.

BACKGROUND

Natriuretic peptides are the primary biomarkers recommended in heart failure (HF) guidelines to risk stratify patients in clinical practice and serve as key eligibility criteria in contemporary clinical trials. However, threshold levels typically do not account for measures of adiposity, such as body mass index (BMI).

OBJECTIVE

The purpose of this study was to evaluate the association between N-terminal pro-B-type natriuretic peptide (NT-proBNP) with clinical outcomes in individuals with heart failure and mildly reduced or preserved ejection fraction (HFmrEF/HFpEF), stratified according to BMI.

METHODS

In this participant-level pooled analysis of 4 global, randomized, outcomes trials including adults with HFmrEF/HFpEF, the association between NT-proBNP and clinical outcomes (cardiovascular death or HF hospitalization, cardiovascular death, and all-cause death) was evaluated according to BMI as a continuous and categorical variable.

RESULTS

Among 14,750 participants (mean age, 72 ± 9 years; 50% female; mean BMI, 30 ± 6 kg/m2; median NT-proBNP, 836 pg/mL), higher baseline BMI was significantly and nonlinearly associated with lower NT-proBNP levels. Over a median follow-up of 2.8 years, each doubling of baseline NT-proBNP was associated with a 40% higher covariate-adjusted rate of cardiovascular death or HF hospitalization (HR: 1.40; 95% CI: 1.36-1.43; P < 0.001); however, this association appeared incrementally blunted with higher baseline BMI (Pinteraction = 0.008). For the same absolute risk of cardiovascular death or HF hospitalization (5 events per 100 person-years), NT-proBNP levels in participants without atrial fibrillation were nearly 3-fold lower among those with BMI ≥35 kg/m2 (158 pg/mL) vs <35 kg/m2 (450 pg/mL). At a contemporary NT-proBNP-based trial eligibility threshold, absolute risk of cardiovascular death or HF hospitalization ranged from 3.5 per 100 person-years among persons with BMI <30 kg/m2 to 7.3 per 100 person-years among those with BMI ≥40 kg/m2.

CONCLUSIONS

In this analysis, current NT-proBNP thresholds substantially underestimated the absolute risk of adverse HF outcomes among persons with higher BMI. These data question single fixed thresholds and instead suggest that lower NT-proBNP cutoffs may more appropriately risk stratify patients with higher BMI. (Irbesartan in Heart Failure and Preserved Ejection Fraction [I-PRESERVE], NCT00095238; Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist [TOPCAT], NCT00094302; Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin Receptor Blocker Global Outcomes in HF with Preserved Ejection Fraction [PARAGON-HF], NCT01920711; Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER], NCT03619213).