Cardiovascular-kidney-metabolic overlap in patients hospitalized for heart failure across the ejection fraction spectrum

Introduction

In clinical trial populations, cardiovascular-kidney-metabolic (CKM) conditions are common among patients with heart failure (HF) and associated with higher risk of adverse outcomes. However, among patients with HF in contemporary US clinical practice, little is known regarding the burden of overlapping CKM conditions, the associated impact on HF outcomes, and whether the relationship with outcomes may differ by ejection fraction (EF) phenotype.

Purpose

To determine the prevalence and overlap of CKM conditions in patients hospitalized for HF in US clinical practice, as well as the associations with in-hospital and post-discharge outcomes by EF phenotype.

Methods

Among patients hospitalized for HF in the Get With The Guidelines – Heart Failure (GWTG-HF) registry from January 2019 to June 2025, presence of up to 4 additional CKM conditions were evaluated in each patient: atherosclerotic cardiovascular disease, chronic kidney disease, diabetes, and obesity (body mass index ≥30 kg/m2). Associations between number of CKM conditions and in-hospital mortality and length of stay (LOS) were examined using multivariable logistic regression. Among patients 65 years and older linked to Medicare claims, associations between CKM overlap and 1-year post-discharge mortality and hospitalization outcomes were assessed in multivariable Cox regression models. All analyses were stratified by EF phenotype (HFrEF ≤40%, HFmrEF 41-49%, HFpEF ≥50%).

Results

Among 725,205 patients hospitalized for HF, overlapping CKM conditions were common across EF phenotypes, and a minority of patients (6.8%) had HF only without any other CKM condition. The median number of CKM conditions in addition to HF was 2 (IQR 1-3). The proportion of HF only was highest in the HFrEF group (8.6% vs. HFmrEF 5.2% vs. HFpEF 5.4%), while the proportion of 4 overlapping CKM conditions plus HF was highest in the HFpEF group (14.6% vs. HFmrEF 14.3% vs. HFrEF 10.2%). Higher number of overlapping CKM conditions was independently associated with higher in-hospital mortality and longer LOS (Figure 1).

Among 123,271 Medicare beneficiaries hospitalized for HF, increasing CKM overlap was independently associated with stepwise increases in risk of post-discharge mortality and readmission (Figure 1, Figure 2). However, the magnitude of the association between CKM overlap and outcomes differed by EF, with CKM multimorbidity generally having the strongest prognostic impact in HFrEF, intermediate impact in HFmrEF, and lesser impact in HFpEF.

Conclusions

In this contemporary cohort of US patients hospitalized for HF, most patients had multiple additional overlapping CKM conditions. Increasing CKM multimorbidity was independently associated with substantial and stepwise increases in mortality and hospitalization risk. Although the association between increasing CKM multimorbidity and adverse outcomes was seen regardless of EF, the prognostic significance was greatest in HFrEF.Relative Risks of Clinical OutcomesFor image description, please refer to the figure legend and surrounding text.Post-discharge Event RatesFor image description, please refer to the figure legend and surrounding text.