Work

HFpEF-ABA score is a more useful enrichment tool than natriuretic peptides in heart failure with preserved ejection fraction

Year: 2025

Type: article

Abstract: Elevated natriuretic peptide (NP) levels are associated with greater risk for heart failure (HF) hospitalization or death in patients with HF with preserved ejection fraction (HFpEF), supporting use as an enrichment criterion to ensure higher event rates in clinical trials.1–4 However, patients with obesity-related HFpEF display lower N-termimal pro-B type natriuretic peptide (NT-proBNP) levels,5 well below the cut points used in contemporary trials.1–4 Because most patients with HFpEF are living with obesity,6 an NP-based eligibility criterion leads to underrepresentation of a large proportion of patients who may benefit from treatment. The HFpEF-ABA score was developed to facilitate diagnosis of HFpEF without requiring NT-proBNP, using three universally available criteria, age, body mass index (BMI), and history of atrial fibrillation (AF),7 and could provide an alternative, NP-agnostic enrichment criterion. In the SUMMIT trial, treatment with the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist tirzepatide decreased the risk of cardiovascular death or worsening HF in patients with obesity-related HFpEF.8 We sought to determine the influence of HFpEF-ABA scores in characterizing patients with HFpEF and their response to treatment with tirzepatide, and specifically evaluate whether it may serve as an alternative to NT-proBNP to enrich for risk of HF events. The primary results of the SUMMIT trial, study protocol, and the statistical analysis plan have been published.8 Briefly, patients with obesity-related HFpEF (EF ≥ 50%, BMI ≥ 30 kg/m2) were randomized 1:1 to placebo or tirzepatide titrated as tolerated to 15.0 mg/week. The co-primary endpoints were the time-to-first adjudicated cardiovascular death or worsening HF and change in KCCQ-CSS at 52 weeks. Baseline HFpEF-ABA score was calculated for each as previously described.7 Patients were categorized into three groups of HFpEF-ABA score: <75%, 75–89%, and ≥90%. Tests to evaluate trends in baseline characteristics were performed using the two-sided Jonckheere–Terpstra test. Risk for the primary endpoint event of worsening HF or cardiovascular death among placebo participants across baseline HFpEF-ABA categories was evaluated by plotting cumulative incidence of worsening HF or cardiovascular death estimated using the Kaplan–Meier method. Primary outcomes were analysed using a time-to-first event approach, using a Cox regression model for each baseline HFpEF-ABA category, adjusted for two covariates (diabetes and NT-proBNP < vs ≥200 pg/mL). Evaluation for trend in the absolute risk reduction with tirzepatide vs placebo for the primary outcome was evaluated by fitting a weighted linear regression model, where the absolute risk difference was treated as the dependent variable and HFpEF-ABA group as the independent variable, using weights equal to 1/SE². Changes in KCCQ-CSS at 52 weeks from baseline were analysed using a mixed-effects model for repeated measures (MMRM). Statistical significance was determined using α=.05. Analyses were performed using SAS Enterprise guide 8.2 (SAS Institute Inc., Cary, NC, USA). Of the 731 patients with obesity-related HFpEF, 219 (30.0%) had HFpEF-ABA score probability < 75%, 215 (29.4%) had HFpEF-ABA ≥ 75% to <90%, and 297 (40.6%) had HFpEF-ABA score ≥ 90%. Patients with higher HFpEF-ABA scores had more severe HFpEF across multiple independent domains, including two-fold higher prevalence of NYHA III-IV symptoms, lower KCCQ-CSS scores (57.1 ± 18.0 vs 55.9 ± 17.6 vs 49.2 ± 18.6, P < .001), higher NT-proBNP levels [91.0 (25.0, 251.0) vs 117.0 (51.0, 340.0) vs 339.0 (156.0, 900.0) pg/mL, P < .001], higher troponin T levels, lower 6 min hall walk distance, and lower estimated glomerular filtration rate (Figure 1). Among patients in the placebo group, the risk of the primary endpoint increased markedly with higher HFpEF-ABA probability score during the study (3.15 to 7.50 to 15.37 per 100 patient-years, log rank P < .001; Figure 1). As compared with patients with HFpEF-ABA < 75%, risk for worsening HF or cardiovascular death was greater for those with HFpEF-ABA 75–89% [hazard ratio (HR) 2.37, 95% CI .96–5.88; P = .063] and those with HFpEF-ABA ≥ 90% (HR 4.49, 95% CI 1.93–10.43; P < .001), even after adjusting for elevated NT-proBNP and diabetes. Heart failure with preserved ejection fraction severity and risk for events by baseline HFpEF-ABA score. (A) Compared with patients with lower HFpEF-ABA score, those with higher scores had poorer 6 min hall walk distance, worse NYHA class, lower estimated glomerular filtration rate, and more severe myocardial injury (troponin T levels) and higher NT-proBNP levels. The 6 min hall walk distance and estimated glomerular filtration rate data are mean, and error bars show standard deviation; NYHA III–IV data are % of total participants; troponin T data are median and error bars show interquartile range. (B) Cumulative incidence plot showing that patients with increasing HFpEF-ABA score had greater risk for the worsening heart failure events or cardiovascular death compared with those with lower scores There was no heterogeneity in the effect of tirzepatide compared with placebo on the risk of worsening HF or cardiovascular death by HFpEF-ABA category (HR .76, .50, and .63, P for trend = .76) and no difference in the effect of tirzepatide compared with placebo on change from baseline in KCCQ-CSS at 52 weeks [+7.31 (2.64, 12.0) vs +8.62 (3.95, 13.3) vs +9.78 (5.10, 14.5), P for trend = .461]. However, because event rates were higher in those with higher HFpEF-ABA score, the absolute risk reduction for worsening HF or cardiovascular death was numerically greater in those with higher scores [absolute risk reduction per 100 person-years (standard error): .71 (1.62) vs 3.63 (2.43) vs 5.74 (3.28), P for trend = .056]. The corresponding numbers needed to treat for 1 year to prevent one primary outcome were therefore 141.0, 27.5, and 17.4. Only 195 (26.7%) of participants in SUMMIT had baseline NT-proBNP levels exceeding eligibility cut-offs used in other contemporary clinical trials in HFpEF (>300 pg/mL or >900 pg/mL in AF).1–4 Compared with patients and NT-proBNP levels below these cut-offs, those with higher levels displayed increased risk for the primary endpoint (12.95 vs 7.38 per 100 patient-years in the placebo group, log rank P = .042). However, only 26.7% of the SUMMIT population and 29.7% of participants with HFpEF-ABA scores ≥ 75% had NT-proBNP levels reaching the cut points for contemporary trials, meaning that 70.3% of those shown to be at high risk and to benefit from tirzepatide would have been excluded relying on this currently employed enrichment criterion. In this post hoc analysis from the SUMMIT trial, higher HFpEF-ABA score identified patients with obesity-related HFpEF who have greater disease severity across multiple domains, with markedly increased risk for HF events, and signal of greater absolute benefit from tirzepatide. The present results apply only to patients with obesity-related HFpEF, and further study is warranted to understand the impact of the HFpEF-ABA score in those with lower BMI. While further validation is warranted in independent cohorts, the present data indicate that in patients with obesity who have suppressed NT-proBNP levels, the HFpEF-ABA score provides a superior, more inclusive, and comprehensive enrichment criterion to the NT-proBNP thresholds that are currently used to identify patients with HFpEF at high risk for events. This can be used in future trials to enhance enrolment velocity and improve generalizability of trial results to patients with HFpEF in the community. B.A.B receives research support from the National Institutes of Health (NIH) and the United States Department of Defense, as well as research grant funding from AstraZeneca, Axon, Corvia, Novo Nordisk, and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations; and is named inventor (US patent no. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. M.R.Z. receives research support from the Department of Veterans Affairs and serves as a consultant for Abbott, Adona Medical, Aria CV, Avery Therapeutics, Inc., Boehringer Ingelheim, Boston Scientific, Cardiovascular Research Foundation (CRF) Clinical Trials Center, CVRx, DIASTOL Therapeutics, LLC, EBR, Edwards, Lilly, GenKardia, Innoventric, KestraMedical, Medtronic, Merck, Morphic Therapeutics, Novartis, Pulnova, Salubris Biotherapeutics, Sonata, SRNALYTICS, INC, V-WAVE, and Vectorious. C.M.K. has served as a consultant for Eli Lilly and Company and Sanofi and has research grants from BMS and Cytokinetics. S.E.L. reported being on the patient selection committee for Corvia and Axon and being a consultant for Novo Nordisk and Lilly. K.H., W.Y., and Y.O. are employed by Eli Lilly and Company. M.M. was formerly employed by Eli Lilly and Company. M.P. has served as a consultant for 89bio, Abbvie, Actavis, Altimmune, Alnylam, Amarin, Amgen, Ardelyx, ARMGO, AstraZeneca, Attralus, Biopeutics, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Lilly, Imara, Medtronic, Moderna, Novartis, Pharmacocosmos, Reata, Regeneron, Roche, and Salamandra. Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization, except for pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the USA and European Union and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data have been made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data-sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, and blank or annotated case report forms, will be provided in a secure data-sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org. The SUMMIT trial was funded by Eli Lilly and Company. B.A.B. is also supported by R01 HL128526, R01 HL162828, and U01 HL160226 from the NHLBI, W81XWH2210245 from the United States Department of Defense, and the Schoen Foundation. The ethics committee at each investigative site approved the trial, and all patients provided written informed consent. The clinicaltrials.gov identifier is NCT05592275.

Source: European Heart Journal

DOI: 10.1093/eurheartj/ehaf663