Clinical implications of chronic heart failure phenotypes defined by cluster analysis

Abstract

Background: Classification of chronic heart failure (HF) is on the basis of criteria that may not adequately capture disease heterogeneity. Improved phenotyping may help inform research and therapeutic strategies.

Objectives: This study used cluster analysis to explore clinical phenotypes in chronic HF patients.

Methods: A cluster analysis was performed on 45 baseline clinical variables from 1,619 participants in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) study, which evaluated exercise training versus usual care in chronic systolic HF. An association between identified clusters and clinical outcomes was assessed using Cox proportional hazards modeling. Differential associations between clinical outcomes and exercise testing were examined using interaction testing.

Results: Four clusters were identified (ranging from 248 to 773 patients in each), in which patients varied considerably among measures of age, sex, race, symptoms, comorbidities, HF etiology, socioeconomic status, quality of life, cardiopulmonary exercise testing parameters, and biomarker levels. Differential associations were observed for hospitalization and mortality risks between and within clusters. Compared with cluster 1, risk of all-cause mortality and/or all-cause hospitalization ranged from 0.65 (95% confidence interval [95% CI]: 0.54 to 0.78) for cluster 4 to 1.02 (95% CI: 0.87 to 1.19) for cluster 3. However, for all-cause mortality, cluster 3 had a disproportionately lower risk of 0.61 (95% CI: 0.44 to 0.86). Evidence suggested differential effects of exercise treatment on changes in peak oxygen consumption and clinical outcomes between clusters (p for interaction <0.04).

Conclusions: Cluster analysis of clinical variables identified 4 distinct phenotypes of chronic HF. Our findings underscore the high degree of disease heterogeneity that exists within chronic HF patients and the need for improved phenotyping of the syndrome. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure; NCT00047437).

Keywords: mortality; prognosis; rehospitalization; socioeconomic.

Figure 1. Risk of Clinical Events Compared with Cluster 1 (Highest Risk)*

Symbols represent hazard ratios and 95 % confidence intervals.

Figure 2. Time to All-Cause Mortality/All-Cause Hospitalization and to All-Cause Mortality

Kaplan-Meier curves, according to patient cluster, that depict (A) the primary endpoint of death or hospitalization (from any cause), and (B) the secondary endpoint of death from any cause.

Central Illustration. Consort diagram showing cluster methodology applied to HF-ACTION study and the four distinct clusters that emerge

Interaction between exercise therapy and patient clusters extracted from the study. Symbols represent Hazard Ratios (HR) and 95 % Confidence Intervals (CI), with HR < 1.00 denoting benefit from exercise, and HR > 1.00 denoting harm.