HFpEF-ABA score trumps NT-proBNP as enrichment tool in obesity-related HFpEF

A post hoc analysis of the SUMMIT trial demonstrates the potential of HFpEF-ABA score as an alternative enrichment tool to NT-proBNP* in individuals with obesity-related heart failure with preserved ejection fraction (HFpEF).

The SUMMIT trial evaluated the effect of tirzepatide on cardiovascular (CV) outcomes in patients with obesity-related HFpEF (EF ≥50 percent, BMI ≥30 kg/m²). [N Engl J Med 2025;392:427-437]

“We sought to determine the influence of HFpEF-ABA scores in characterizing patients with HFpEF and their response to tirzepatide and specifically evaluate whether it may serve as an alternative to NT-proBNP to enrich for risk of HF events,” the investigators said.

In SUMMIT, 731 participants were randomized 1:1 to tirzepatide or placebo. In this analysis, participants were classified according to baseline HFpEF-ABA score of <75, 75–90, and ≥90 percent (n=219, 215, and 297, respectively). The coprimary endpoints were time-to-first adjudicated CV death or worsening HF and change in KCCQ-CSS** at 52 weeks. [Eur Heart J 2025;46:4607-4609]

Higher HFpEF-ABA scores correlated with more severe HFpEF across multiple independent domains, including a higher prevalence of NYHA*** III–IV symptoms, higher NT-proBNP and troponin T levels, and lower KCCQ-CSS scores, 6-min hall walk distance, and estimated glomerular filtration rate (p<0.0001 for all).

In the placebo group, the risk of the primary outcome substantially increased as HFpEF-ABA scores increased (3.15, 7.5, and 15.37/100 patient-years [PY] for <75, 75–90, and ≥90 percent, respectively; p_log-rank<0.001).

Compared with the HFpEF-ABA <75 percent subgroup, the risk for worsening HF or CV death was greater in the HFpEF-ABA 75–89 percent (hazard ratio [HR], 2.37; p=0.063) and ≥90 percent (HR, 4.49; p<0.001) subgroups, even after adjusting for elevated NT-proBNP and diabetes.

Higher NT-proBNP levels

Over a quarter (26.7 percent) of participants had baseline NT-proBNP levels that exceeded eligibility cutoffs used in contemporary trials in HFpEF (>300 or >900 pg/mL in atrial fibrillation [AF]). [N Engl J Med 2019;381:1609-1620; N Engl J Med 2021;385:1451-1461; N Engl J Med 2022;387:1089-1098; N Engl J Med 2024;391:1475-1485]

Compared with patients with NT-proBNP levels below these cutoffs, those with higher levels had an increased risk for the primary endpoint (12.95 vs 7.38/100 PY in the placebo arm; p_log-rank=0.042).

However, only 26.7 percent of the population and 29.7 percent of those with HFpEF-ABA score ≥75 percent had NT-proBNP levels reaching the cutoff points for contemporary trials, the investigators noted. “This means that 70.3 percent of those shown to be at high risk and to benefit from tirzepatide would have been excluded relying on this currently employed enrichment criterion.”

A more inclusive enrichment criterion

In HFpEF, higher NP levels are tied to a greater risk for HF hospitalization or death. This supports the use of elevated NT-proBNP levels as an enrichment criterion to ensure higher event rates in clinical trials. However, individuals with obesity-related HFpEF have NT-proBNP levels that are well below the cutoff points used in contemporary trials, the researchers noted.

“Because most HFpEF patients also have obesity, an NP-based eligibility criterion leads to underrepresentation of a large proportion of patients who may benefit from treatment,” they pointed out. “The HFpEF-ABA score was developed to facilitate HFpEF diagnosis without requiring NT-proBNP, using three universally available criteria (age, BMI, AF history) and could provide an alternative, NP-agnostic enrichment criterion.”

However, as the study was limited to patients with obesity-related HFpEF, the researchers recommended further investigation on the effect of the HFpEF-ABA score among those with lower BMI.

Pending further validation, the current data suggest that in obese patients with suppressed NT-proBNP levels, the HFpEF-ABA score provides a superior, more inclusive, and comprehensive enrichment criterion to the NT-proBNP thresholds currently used to identify high-risk HFpEF patients, said the researchers.