Introduction and objectives To identify phenotypes in heart failure with preserved ejection fraction (HFpEF), compare mortality, and investigate whether treatments have different effects according to phenotype.

Methods We performed a secondary analysis of 8161 patients with HFpEF included in Spanish cardiology (INCLIVA), internal medicine (RICA), and emergency (EAHFE) registries. Phenotypic clusters based on 16 baseline characteristics were identified using latent class analysis. We analyzed crude and treatment-adjusted 1-year survival, the associations between each treatment and mortality, and their interactions with phenotype.

Results We identified 4 distinct clusters. One-year mortality was 18.7%. Cluster 4 (younger women with a valvular heart disease phenotype) had the lowest mortality (13.7%; reference category), which increased progressively in cluster 2 (cardiometabolic phenotype; mortality: 15.7%; adjusted HR, 1.28; 95%CI, 1.06-1.54), cluster 3 (very elderly female phenotype; mortality: 20.4%; adjusted HR, 1.63; 95%CI, 1.40-1.90), and cluster 1 (male cardiorespiratory phenotype ; mortality: 24.0%; adjusted HR, 1.81; 95%CI, 1.53-2.13). The results were very similar when each registry was analyzed individually. Treatment with renin-angiotensin system inhibitors was associated with better survival in all clusters, beta-blockers were beneficial in cluster 1, and anticoagulants in cluster 4. However, none of the treatments shoed a differential association with prognosis according to phenotype.

Conclusions This study defines 4 HFpEF phenotypes with significantly different prognoses. Among the treatments analyzed, only renin-angiotensin system inhibitors seemed to have a generalized survival benefit, and none demonstrated a differential effect based on phenotype.

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