Evidence-Based Application of Natriuretic Peptides in the Evaluation of Chronic Heart Failure With Preserved Ejection Fraction in the Ambulatory Outpatient Setting

Background: Plasma NT-proBNP (N-terminal pro-B-type natriuretic peptide) is commonly used to diagnose heart failure with preserved ejection fraction (HFpEF), but its diagnostic performance in the ambulatory/outpatient setting is unknown because previous studies lacked objective reference standards.

Methods: Among patients with chronic dyspnea, diagnosis of HFpEF or noncardiac dyspnea was determined conclusively by exercise catheterization in a derivation cohort (n=414), multicenter validation cohort 1 (n=560), validation cohort 2 (n=207), and a nonobese Japanese validation cohort 3 (n=77). Optimal NT-proBNP cut points for HFpEF rule out (optimizing sensitivity) and rule in (optimizing specificity) were derived and tested, stratified by obesity and atrial fibrillation. Derived cut points were tested in 3 additional validation cohorts (cohorts 4-6) in whom HFpEF was diagnosed by resting catheterization only (n=260), previous hospitalization for heart failure (n=447), or exercise echocardiography (n=517), respectively.

Results: Current recommended rule-out NT-proBNP threshold <125 pg/mL had 82% sensitivity (95% CI, 77%-88%) with a body mass index (BMI) <35 kg/m², decreasing to 67% (95% CI, 58%-77%) with a BMI ≥35 kg/m². A lower rule-out NT-proBNP threshold <50 pg/mL displayed good sensitivity with a BMI <35 kg/m² (97% [95% CI, 95%-99%]), with a modest decline in sensitivity with a BMI ≥35 kg/m² (86% [95% CI, 79%-93%]); diagnostic thresholds were confirmed in validation cohorts 1 and 2 (91% [95% CI, 88%-95%] and 86% [95% CI, 80%-93%] with a BMI <35 kg/m²; 80% [95% CI, 74%-87%] and 84% [95% CI, 74%-93%] with a BMI ≥35 kg/m²). Current consensus age- and BMI-stratified rule-in thresholds demonstrated only 65% specificity (95% CI, 57%-72%). Rule-in NT-proBNP threshold ≥500 pg/mL had 85% specificity (95% CI, 78%-91%) with a BMI <35 kg/m² (87% [95% CI, 80%-94%] and 90% [95% CI, 81%-99%] in validation cohorts), with 100% specificity at a BMI ≥35 kg/m² (93% [95% CI, 81%-100%] and 100% in validation cohorts). With a BMI ≥35 kg/m², lower rule-in thresholds (≥220 pg/mL) provided good specificity (88% [95% CI, 73%-100%]; 93% [95% CI, 81%-100%] and 100% in validation cohorts). Findings were consistent in validation cohorts 3 through 6 (sensitivity of <50 pg/mL, 93%-98%; specificity of ≥500 pg/mL, 82%-89%). NT-proBNP provided no incremental discrimination among patients with history of AF; ≥98% of patients with AF and dyspnea were found to have HFpEF in our cohorts.

Conclusions: In patients with chronic unexplained dyspnea, current rule-in and rule-out NT-proBNP diagnostic thresholds lead to unacceptably high error rates, with important interactions by obesity and AF status. In our study, NT-proBNP provided little value in those with AF and dyspnea because the presence of AF is by itself a robust biomarker of HFpEF. Use of separate rule-in and rule-out diagnostic thresholds stratified by BMI reduces miscategorization and can guide more appropriate use of exercise testing for possible HFpEF.