Improving stroke risk prediction in atrial fibrillation with circulating biomarkers: the CHA2DS2-VASc-Biomarkers model

Abstract

Background: Anticoagulation reduces ischemic stroke in atrial fibrillation (AF) but increases bleeding. Existing risk calculators guiding anticoagulation decisions in AF have substantial limitations.

Objectives: To determine whether biomarkers of stroke risk for general populations are associated with stroke risk in AF and improve predictive performance of the CHA₂DS₂-VASc (Congestive heart failure, Hypertension, Age >74, Diabetes, prior Stroke or transient ischemic attack or thromboembolism, Vascular disease, Age 65-74, Sex category) score.

Methods: The REasons for Geographic And Racial Differences in Stroke (REGARDS) is a prospective cohort study of 30 239 adults enrolled in 2003 to 2007 and monitored for stroke. Participants with AF not taking anticoagulants and with no prior stroke history were studied. Nine circulating biomarkers were measured in stored baseline samples. Cox models, adjusted for demographics and stroke risk factors estimated associations of each biomarker with incident stroke. Then, models with CHA₂DS₂-VASc score alone or adding biomarkers were compared using tests of fit (likelihood ratio test and Akaike information criterion) and risk discrimination (continuous net reclassification index, [NRI^>0]).

Results: Among 2411 participants with AF (median age 69 years, 55% female, 36% Black), 163 (7%) developed first-time ischemic stroke over 13 years. Higher N-terminal pro-B-type natriuretic peptide, growth differentiation factor 15, cystatin C, interleukin 6, and lipoprotein (a) were independently associated with higher stroke risk. Biomarkers substantially improved CHA₂DS₂-VASc model fit (change in Akaike information criterion -13, P < .001) and predictive ability (5-year NRI^>0 0.42). Adding only N-terminal pro-B-type natriuretic peptide and growth differentiation factor 15 yielded the best model fit and a similar NRI^>0 compared with all biomarkers.

Conclusions: Five biomarkers were associated with stroke risk in AF, and 2 of these improved CHA₂DS₂-VASc performance. This improved CHA₂DS₂-VASc-Biomarkers score can allow better selection of patients for anticoagulation to reduce stroke in AF.

Keywords: atrial fibrillation; biomarkers; cohort study; ischemic stroke; risk assessment.