Serial measurement of biomarkers and the risk of stroke or systemic embolism and bleeding in patients with atrial fibrillation in ENGAGE AF-TIMI 48
Authors: Oyama K , Giugliano R , Berg D , Ruff C , Tang M , Murphy S , Lanz H , Grosso M , Antman E , Braunwald E , Morrow D 
Published: November 2020

Abstract

Background
Patients with atrial fibrillation (AF) have progressive cardiac structural changes that may be manifest by biomarkers of myocardial injury and hemodynamic stress. Baseline values of hsTnT (high-sensitivity troponin T), and NT-proBNP (N-terminal pro-brain natriuretic peptide) are associated with stroke risk and GDF-15 (growth differentiation factor-15) is associated with bleeding risk in patients with AF. However, the variability of these biomarkers over time and their associations with stroke or systemic embolism events (S/SEE) and bleeding in patients with AF remain unclear.

Purpose
We examined whether patients with AF demonstrate detectable changes in these biomarkers over 12 months and whether such changes from baseline to 12 months are associated with the subsequent risk of S/SEE (hsTnT, NT-proBNP) and bleeding (GDF-15).

Methods
ENGAGE AF-TIMI 48 was a multinational randomized trial of the oral factor Xa inhibitor edoxaban in patients with atrial fibrillation and a CHADS2 score ≥2. We performed a nested prospective biomarker study in 6062 patients, analyzing hsTnT, NT-proBNP, and GDF-15 at baseline and 12 months. Event rates were estimated and displayed with annualized event rates after 12 months.

Results
Of 6062 patients, hsTnT was dynamic in 46.9% (≥2 ng/L change), NT-proBNP in 51.9% (≥200 pg/L change), GDF-15 in 45.6% (≥300 pg/L change) between baseline and 12 months. In addition, 7.7% in hsTnT shifted from low-&gt;high categories, 9.4% in NT-proBNP from low-&gt;high, 10.6% in GDF-15 from low-&gt;high over 12 months (Figure). Elevated hsTnT (≥14 ng/L) and NT-proBNP (≥900 pg/L) either at baseline or at 12 months were independently associated with higher rates of subsequent S/SEE, and elevated GDF-15 (≥1800 pg/L) either at baseline or at 12 months were independently associated with higher rates of subsequent bleeding (P&lt;0.001 for each). In a Cox regression model, the absolute changes in log2-transformed hsTnT and NT-proBNP were associated with increased risk of S/SEE (adj-HR, 1.75; 95% CI, 1.38–2.23; p&lt;0.001, and adj-HR, 1.31; 95% CI, 1.11–1.55; p=0.002, respectively) and log2-transformed GDF-15 with bleeding (adj-HR, 1.42; 95% CI, 1.04–1.92; p=0.025). Analyzed in a categorical manner (Figure), patients who increased hsTnT or NT-proBNP between baseline and 12 months or had high hsTnT or NT-proBNP at both timepoints were at higher risk for S/SEE (adj-HR 1.87 and 1.50 for hsTnT; adj-HR 1.80 and 2.59 for NT-proBNP, respectively). Patients with persistently elevated GDF-15 appeared to be at higher risk for bleeding (adj-HR,1.35) (Figure).

Conclusions
Serial assessment of hsTnT, NT-proBNP, and GDF-15 revealed a substantial proportion of patients with AF had dynamic values. Patients with either persistently elevated or dynamic values were at higher risk of adverse clinical outcomes. Those biomarkers may play a role in personalizing preventive strategies in patients with AF based on risk.
Change in biomarkers and event rate

Funding Acknowledgement
Type of funding source: Private company. Main funding source(s): Daiichi Sankyo Pharma Development