Phenotypic clusters and sacubitril/valsartan in heart failure with preserved ejection fraction: a PARAGON-HF substudy
W O N S E Kim, M I N J A E Yoon, W O O N G Kook, P A R T Jin JooAbstract
Background
Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with substantial variability in prognosis and responses to pharmacologic therapy within the patients. Patient clustering may enable improved prognostic stratification and identification of differential treatment responses.
Purpose
To derive machine learning–based HFpEF phenogroups and assess their utility for predicting prognosis and treatment response.
Methods
Using data from 4,796 patients enrolled in the PARAGON-HF trial, we identified three distinct clinical phenogroups using a hierarchical agglomerative clustering algorithm based on 33 baseline characteristics. The primary outcome was a composite of total hospitalizations for heart failure and death from cardiovascular causes. Clinical outcomes were compared across phenogroups for the primary endpoint, and the treatment response to sacubitril/valsartan versus valsartan was evaluated by phenogroup.
Results
Phenogroup 1 (n=832) was characterized by younger age, a higher proportion of men, a greater prevalence of ischemic etiology, and lower LVEF. Phenogroup 2 (n=2,666) comprised older patients with a higher proportion of women, a higher prevalence of atrial fibrillation, and higher NT-proBNP levels. Phenogroup 3 (n=1,209) exhibited a higher prevalence of obesity and diabetes, and lower NT-proBNP levels. Compared with phenogroups 1 or 2, phenogroup 3 had the highest risk of primary composite outcome and all-cause mortality (all P <0.05). Sacubitril/valsartan treatment was associated with a more pronounced reduction in the risk of the primary endpoint in phenogroup 2 (rate ratio 0.78 [95% CI 0.63-0.96]; p for interaction = 0.052).
Conclusions
Three distinct HFpEF phenogroups with different prognoses and differential responses to sacubitril/valsartan were identified. These findings suggest distinct underlying pathophysiologic mechanisms among clinically identifiable HFpEF phenogroups and support potential for phenogroup-specific targeted therapeutic interventions.Characterization of Heart Failure PhenogFor image description, please refer to the figure legend and surrounding text.Differential Treatment Efficacy of SacubFor image description, please refer to the figure legend and surrounding text.