Serial assessment of biomarkers and the risk of stroke or systemic embolism and bleeding in patients with atrial fibrillation in the ENGAGE AF-TIMI 48 trial

Abstract

Aims: We investigated whether patients with atrial fibrillation (AF) demonstrate detectable changes in biomarkers including high-sensitivity troponin T (hsTnT), N-terminal B-type natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) over 12 months and whether such changes from baseline to 12 months are associated with the subsequent risk of stroke or systemic embolic events (S/SEE) and bleeding.

Methods and results: ENGAGE AF-TIMI 48 was a randomized trial of the oral factor Xa inhibitor edoxaban in patients with AF and a CHADS2 score of ≥2. We performed a nested prospective biomarker study in 6308 patients, analysing hsTnT, NT-proBNP, and GDF-15 at baseline and 12 months. hsTnT was dynamic in 46.9% (≥2 ng/L change), NT-proBNP in 51.9% (≥200 pg/mL change), GDF-15 in 45.6% (≥300 pg/mL change) during 12 months. In a Cox regression model, upward changes in log2-transformed hsTnT and NT-proBNP were associated with increased risk of S/SEE [adjusted hazard ratio (adj-HR) 1.74; 95% confidence interval (CI) 1.36-2.23 and adj-HR 1.27; 95% CI 1.07-1.50, respectively] and log2-transformed GDF-15 with bleeding (adj-HR 1.40; 95% CI 1.02-1.92). Reassessment of ABC-stroke (age, prior stroke/transient ischaemic attack, hsTnT, and NT-proBNP) and ABC-bleeding (age, prior bleeding, haemoglobin, hsTnT, and GDF-15) risk scores at 12 months accurately reclassified a significant proportion of patients compared with their baseline risk [net reclassification improvement (NRI) 0.50; 95% CI 0.36-0.65; NRI 0.42; 95% CI 0.33-0.51, respectively].

Conclusion: Serial assessment of hsTnT, NT-proBNP, and GDF-15 revealed that a substantial proportion of patients with AF had dynamic values. Greater increases in these biomarkers measured over 1 year are associated with important clinical outcomes in anticoagulated patients with AF.

Trial registration: ClinicalTrials.gov NCT00781391.

Keywords: Atrial fibrillation; Biomarkers; Haemorrhage; Risk assessment; Stroke.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Figures

Serial assessment of biomarkers and the risk of stroke or systemic embolism and bleeding in patients with atrial fibrillation. hsTnT, high-sensitivity troponin T; NT-proBNP, N-terminal pro-brain natriuretic peptide; GDF-15, growth differentiation factor-15; AF, atrial fibrillation; ABC, age, biomarker, and clinical history.

Figure 1

Distribution of patients by the absolute change in biomarker concentrations between baseline and 12 months. One percentage of observations is truncated from each side for illustrative purposes only in this figure. GDF-15, growth differentiation factor-15; hsTnT, high-sensitivity troponin T; NT-proBNP, N-terminal pro-B-type natriuretic peptide.

Figure 2

Biomarker values at 12 months and annualized subsequent event rates after 12 months. CI, confidence interval; ; GDF-15, growth differentiation factor-15; HR, hazard ratio; hsTnT, high-sensitivity troponin T; NT-proBNP, N-terminal pro-B-type natriuretic peptide.

Figure 3

Changes in biomarkers from baseline to 12 months as a continuous variable and subsequent risks of clinical events. Example patients in panel A indicate specific changes in high-sensitivity troponin T; #1 with 8 ng/L at baseline and 16 ng/L at 12 months, #2 with 31 ng/L at baseline and 45 ng/L at 12 months, #3 with 33 ng/L at baseline and 23 ng/L at 12 months, and #4 with 17 ng/L at baseline and 8 ng/L at 12 months. ; GDF-15, growth differentiation factor-15; hsTnT, high-sensitivity troponin T; NT-proBNP, N-terminal pro-B-type natriuretic peptide.

Figure 4

Annualized subsequent event rates stratified by age, biomarker, and clinical history score at baseline and 12 months for stroke or systemic embolism (A) and major bleeding (B). ABC, age, biomarker, and clinical history.