Role of Biomarker-Guided Treatment in Heart Failure

Study Questions:

What is the role of circulating biomarkers on up-titration of angiotensin-converting enzyme (ACE) inhibitor/angiotensin-receptor blocker (ARB), beta-blocker, and mineralocorticoid receptor antagonist (MRA) doses in heart failure?


The cohort was comprised of 2,516 patients with worsening heart failure from the BIOSTAT-CHF study. The patients were aged >18 years with symptoms of new-onset or worsening heart failure, confirmed either by a left ventricular ejection fraction (LVEF) of ≤40% or B-type natriuretic peptide (BNP) and/or N-terminal pro–B-type natriuretic peptide (NT-proBNP) plasma levels >400 pg/ml or >2000 pg/ml, respectively. Primary patient outcome in BIOSTAT-CHF was the first occurrence of all-cause mortality or heart failure-related hospitalization. Survival time was calculated from date of inclusion in BIOSTAT-CHF to date of death/heart failure hospitalization or date of censoring. The study authors compared clinical outcomes between three theoretical treatment scenarios: A) all patients are up-titrated to >50% of recommended doses, B) patients are up-titrated according to a biomarker-based treatment selection model, and C) no patient is up-titrated to >50% of recommended doses. Only patients who were followed for ≥3 months were included in the present analysis. They conducted multivariable Cox regression using 161 biomarkers and their interaction with treatment, weighted for treatment-indication bias to estimate the expected number of deaths and/or heart failure hospitalizations at 24 months for all three scenarios.


The study authors found that estimated death/hospitalization rates in 1,802 patients with available biomarkers were 16%, 16%, and 26%, respectively in ACE inhibitor/ARB up-titration scenarios A, B, and C. Patients not benefitting from ACE inhibitor/ARB up-titration were younger, more frequent smokers, with less atrial fibrillation; higher hemoglobin and blood urea nitrogen (BUN), but lower heart rate and NT-proBNP levels. Similar rates for beta-blocker and MRA up-titration scenarios A, B, and C were 23%, 19%, and 24%, and 12%, 11%, and 24%, respectively. Patients not benefitting from beta-blocker up-titration were older, leaner, more frequently smokers or former smokers. They also had less ischemic HF, but more myocardial infarctions, and other comorbidities. They also had significantly higher LVEF, (NT-pro)BNP, BUN and creatinine levels, and lower diastolic blood pressure, heart rate, hemoglobin, and estimated glomerular filtration rate levels. If up-titration was successful in all patients, an estimated 9.8 (95% confidence interval [CI], 7.1-12.6), 1.3 (95% CI, -3 to 5.7), and 12.3 (8.1-16.5) events per 100 treated patients could be prevented at 24 months by ACE inhibitor/ARB, beta-blocker, and MRA therapy. Similar numbers were 9.9 (95% CI, 7.2-12.6), 4.7 (95% CI, 2.2-7.1), and 13.1 (95% CI, 9.4-16.8) if the up-titration treatment decision was based on a biomarker-based treatment-selection model. The authors estimated that 1 in 50, 1 in 3, and 1 in 8 patients would not benefit from ACE inhibitor/ARB, beta-blocker, or MRA up-titration, but their mortality/hospitalization hazards would not increase much by up-titration.


The authors concluded that up-titrating patients with heart failure based on biomarker values might have resulted in fewer deaths and/or hospitalizations compared to a hypothetical scenario in which all patients were successfully up-titrated.


This interesting simulation suggests that a multimarker-guided therapy is more successful in achieving up-titration of guideline-directed medical therapy, and therefore, would have resulted in improved mortality and reduced HF hospitalizations. Prospective studies are required to confirm these important findings.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Adrenergic beta-Antagonists, Angiotensin-Converting Enzyme Inhibitors, Angiotensin Receptor Antagonists, Atrial Fibrillation, Biological Markers, Blood Pressure, Blood Urea Nitrogen, Comorbidity, Creatinine, Glomerular Filtration Rate, Heart Failure, Heart Rate, Hemoglobins, Mineralocorticoid Receptor Antagonists, Myocardial Infarction, Natriuretic Peptide, Brain, Peptide Fragments, Stroke Volume, Treatment Outcome

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