Clinical Implications of Chronic Heart Failure Phenotypes Defined by Cluster Analysis

Abstract

BACKGROUND Classification of chronic heart failure (HF) is based on criteria that may not adequately capture disease heterogeneity. Improved phenotyping may help inform research and therapeutic strategies. OBJECTIVE 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 HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training), evaluating exercise training versus usual care in chronic systolic HF. Association between identified clusters and clinical outcomes was performed using Cox proportional hazards modeling. Differential associations between clinical outcomes and exercise testing were examined using interaction testing. RESULTS Ranging in size from 248 to 773, four clusters were identified whose patients varied considerably along 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. To illustrate, compared with cluster 1, risk of all-cause mortality/all-cause hospitalization ranged from 0.65 (0.54 to 0.78) for cluster 4 to 1.02 (0.87 to 1.19) for cluster 3. However, for all-cause mortality, cluster 3 had disproportionately lower risk 0.61 (0.44 to 0.86). Evidence suggested differential effects of exercise treatment on changes in peak VO2 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 a need for improved phenotyping.

Inflammatory biomarkers and effect of exercise on functional capacity in patients with heart failure: Insights from a randomized clinical trial

“…[26][27][28] In the HF-ACTION study, patients with heart failure were classified through cluster analysis in four different phenotypes that differed from each other regarding their overall prognosis and the effect of exercise on cardiovascular mortality and heart failure hospitalization. 27 The patients in the phenotype that displayed the largest peak _ VO 2 improvement with three-month exercise were the youngest, mainly had heart failure from non-ischemic causes and apparently less advanced heart failure, as reflected by low _ VE-_ VCO 2 slope in the CPET and low blood levels of galectin-3, in concordance with our findings. Another sub-analysis from the HF-ACTION study showed an association of elevated or worsening high-sensitivity C-reactive protein and N-terminal pro-B-type natriuretic peptide blood levels with lower peak _ VO 2 over time.…”

The Future of Heart Failure Diagnosis, Therapy, and Management

“…As an example, Ahmad and colleagues leveraged the highly annotated demographic and clinical baseline data, and adjudicated outcomes in the National Heart, Lung, and Blood Institute (NHLBI)-sponsored Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) trial to identify 4 clusters of patients with HFrEF with distinct clinical characteristics and differing outcomes. 30 In concept, such data could be used to select better patients for trials of new therapies, not only by enriching the outcome event rate, but also to target better therapies, if the clinical cluster can be linked with a distinct pathophysiologic driver that might be amenable to focused intervention.…”

Machine Learning Methods Improve Prognostication, Identify Clinically Distinct Phenotypes, and Detect Heterogeneity in Response to Therapy in a Large Cohort of Heart Failure Patients

“…In medicine, these methodologies can use a data‐driven approach to re‐examine phenotyping of complex diseases such as HF 11. Recently, these methods identified distinct phenotypes of HF with reduced and preserved ejection fraction (HFrEF and HFpEF) among 1619 patients with HFrEF enrolled in the HF‐ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) clinical trial and 397 patients seen at the HF clinic at outpatient clinic of the Northwestern University HFpEF Program 12, 13…”