712 inflammation, haemostasis and extracellular matrix in the stratification of bleeding and thrombotic risk of atrial fibrillation on oral anticoagulant therapy: insights from strat-af study

Abstract Background In anticoagulated atrial fibrillation patients, the validity of models recommended for the stratification of the risk ratio between benefits and hemorrhage risk is limited. We hypothesize that biological markers – both circulating and neuroimaging-based – and their possible interaction, might improve the prediction of bleeding risk in atrial fibrillation patients under treatment with any type of oral anticoagulant. Methods The Strat-AF study is an observational, prospective, single-center hospital-based study enrolling patients with atrial fibrillation, aged 65 years or older, and with no contraindications to undergo magnetic resonance imaging. Recruited patients are evaluated by means of a comprehensive protocol, with clinical, cerebral magnetic resonance imaging and circulating biomarkers assessment. The main outcomes are the evaluation of cerebral microangiopathy using MRI (lacunar infarcts, non-lacunar infarcts, microbleeds, hyperintensity of the white matter, SVDs [small vessel disease score]) and the onset of ischemic or hemorrhagic stroke related to the levels of circulating biomarkers of inflammation (IL-6, IL-8, TNFα, IL-4, IL-10, CCL2, CXCL10, ICAM-1, VCAM-1, VEGF), haemostasis (PAI-1, CLT, vWF) and extracellular matrix remodeling (MMP-2,-7,-8,-9,-12, TIMP-1,-2,-3,-4). Starting from September 2017, 191 patients (mean age 78.1±6.7, range 65-97; 65.3% males) were enrolled. 56 patients (29.3%) were on vitamin K antagonists, and 135 (70.7%) were on direct oral anticoagulants. Follow-up clinical evaluation and brain MRI were performed at 18 months. Results At multivariate analysis, adjusted for age, sex, CHA2DS2-VASc, HAS-BLED and type of anticoagulant, independent predictors were: low levels of vWF and elevated levels of TIMP-2 for microbleeds [OR:0.62 95%CI(0.42-0.89), p=0.011and OR:1.25 (1.01-1.77), p=0.049 respectively]; elevated levels of IL-6 and TIMP-4 for hyperintensity of white matter [OR: 1.55 (1.01-2.58), p=0.049 and OR: 1.44 (1.01-2.07), p=0.047 respectively]; elevated levels of MMP-2 and of TIMP-1 and TIMP-2 for lacunar infarcts [OR: 1.33 (1.01-1.89), p=0.049, OR: 1.48(1.01-2.18), p=0.048 and 1.50 (1.05-2.16), p=0.028 respectively]; elevated levels of TIMP-1, TIMP-2, TIMP-3 for the appearance of at least 1 new lesion according to the SVD score [OR: 1.48 (1.01-2.19), p=0.046, OR:1.53 (1.05-2.23), p=0.028 and OR: 1.58 (1.09-2.31), p=0.016 respectively]. Conclusions The Strat-AF study may be an essential step towards the exploration of the role of a combined clinical biomarker or multiple biomarker models in predicting stroke risk in atrial fibrillation and might sustain the incorporation of such new markers in the existing stroke prediction schemes by the demonstration of a greater incremental value in predicting stroke risk and improvement in clinical outcomes in a cost-effective fashion.