Blood Clotting Markers and Heart Ultrasound in People With Device-Detected Atrial Fibrillation (DDAF-HEV)

Device-Detected Atrial Fibrillation - Haemostatic Profile and Echocardiographic Variables

The purpose of this observational study is to investigate whether blood tests related to blood clotting are associated with established clinical stroke risk scores, the total amount of device-detected atrial fibrillation recorded by an implanted cardiac device, and ultrasound measurements of the heart in people with device-detected atrial fibrillation. The study will also evaluate whether these baseline measurements are associated with future clinical outcomes and may improve future stroke risk assessment.

Device-detected atrial fibrillation is an irregular heart rhythm detected by implanted cardiac devices such as pacemakers, implantable cardiac monitors, and implantable defibrillators. It is often brief and does not cause symptoms. Although it increases the risk of stroke and systemic embolism, the risk is lower than in people with clinically diagnosed atrial fibrillation. As a result, it remains difficult to identify which patients are most likely to benefit from blood-thinning medication, which reduces the risk of stroke but also increases the risk of bleeding.

The study will include 222 participants with implanted cardiac devices, including 111 participants with device-detected atrial fibrillation and 111 age-, sex-, and cardiac device indication-matched control participants without device-detected atrial fibrillation. At baseline, participants will undergo blood sampling, ultrasound examination of the heart, and routine device interrogation. Information on medical history and established clinical stroke risk factors will also be collected. The implanted cardiac device will be used to determine the total amount of device-detected atrial fibrillation recorded during the year before study inclusion.

The baseline analyses will investigate whether established clinical stroke risk scores, the total amount of device-detected atrial fibrillation, and heart ultrasound findings are associated with changes in blood clotting that may indicate an increased tendency to form blood clots. The study will evaluate both primary and additional blood clotting markers to improve the understanding of the biological mechanisms underlying thromboembolic risk in device-detected atrial fibrillation.

Participants will subsequently be followed for 10 years to determine whether baseline blood clotting markers, the total amount of device-detected atrial fibrillation, heart ultrasound findings, and clinical stroke risk scores are associated with future clinical outcomes, including stroke, systemic embolism, hospitalization, death, progression to clinically diagnosed atrial fibrillation, and initiation of oral anticoagulant therapy.

The findings may improve the understanding of thromboembolic risk in people with device-detected atrial fibrillation and support the development of more individualized approaches to future stroke risk assessment and treatment.

Study Overview

• Status: Recruiting
• Conditions: Subclinical Atrial Fibrillation; Atrial High Rate Episodes; Device-detected Atrial Fibrillation

Detailed Description

Scientific Rationale Device-detected atrial fibrillation (DDAF) is associated with an increased risk of stroke and systemic embolism, although the risk is lower than in patients with clinically diagnosed atrial fibrillation. Consequently, it remains challenging to identify which patients are most likely to benefit from oral anticoagulant therapy while minimizing the risk of bleeding. Current stroke risk assessment in patients with device-detected atrial fibrillation relies primarily on clinical risk scores and does not incorporate haemostatic biomarkers, the burden of device-detected atrial fibrillation, or echocardiographic markers of atrial remodeling that may contribute to thromboembolic risk. This study aims to improve the understanding of thromboembolic risk in patients with DDAF and to evaluate whether integrating clinical stroke risk scores, DDAF burden, advanced echocardiographic variables, and haemostatic biomarkers may improve future stroke risk assessment.

Study Design This is a prospective, single-center observational cohort study conducted at the Department of Cardiology, Esbjerg and Grindsted Hospital, University Hospital of Southern Denmark, in collaboration with the Unit for Thrombosis Research, Department of Clinical Diagnostics.

The study consists of a single prospective observational cohort with three prespecified baseline analyses followed by a prospective 10-year longitudinal follow-up. A total of 222 participants will be enrolled, including 111 participants with device-detected atrial fibrillation and 111 control participants matched for age, sex, and indication for cardiac device implantation.

Baseline Assessments At baseline, all participants will undergo standardized blood sampling, comprehensive transthoracic echocardiography, and collection of demographic and clinical information. Device interrogation will be performed to quantify the burden of device-detected atrial fibrillation. Clinical thromboembolic risk will be assessed using the CHA₂DS₂-VASc score. In addition, the ABC-stroke score will be calculated to evaluate its associations with haemostatic biomarkers and subsequent clinical outcomes in participants with device-detected atrial fibrillation.

Independent variables in the prespecified baseline analyses include the CHA₂DS₂-VASc score, the ABC-stroke score, burden of device-detected atrial fibrillation, and advanced echocardiographic variables.

The baseline analyses are designed to address three prespecified objectives. Together, these analyses are intended to determine whether established clinical stroke risk scores, burden of device-detected atrial fibrillation, and cardiac structural and functional abnormalities are associated with a more prothrombotic haemostatic profile.

1. To investigate whether the primary haemostatic biomarkers, endogenous thrombin potential (ETP) and von Willebrand factor antigen, differ between participants with device-detected atrial fibrillation and matched controls and whether they are associated with the CHA₂DS₂-VASc and ABC-stroke risk scores. Secondary analyses will evaluate associations between additional haemostatic biomarkers and the clinical stroke risk scores.
2. To investigate whether the primary haemostatic biomarkers are associated with the burden of device-detected atrial fibrillation. Secondary analyses will evaluate associations between DDAF burden and additional haemostatic biomarkers.
3. To investigate whether the primary haemostatic biomarkers are associated with advanced echocardiographic variables, including left atrial size and function. Secondary analyses will evaluate associations between echocardiographic variables and additional haemostatic biomarkers.

The primary cross-sectional outcome measures are endogenous thrombin potential (ETP) and von Willebrand factor antigen. Secondary cross-sectional outcome measures comprise additional biomarkers of coagulation and fibrinolysis.

Longitudinal Follow-up Participants will subsequently be followed for 10 years through electronic health records, routine device interrogation reports, and Danish national health registries. Follow-up data will be collected every second year to evaluate whether baseline primary and secondary haemostatic biomarkers, DDAF burden, clinical stroke risk scores, and echocardiographic findings are associated with subsequent stroke, systemic embolism, hospitalization, death, progression to clinically diagnosed atrial fibrillation, and initiation of oral anticoagulant therapy.

Statistical Analysis The sample size was calculated to provide 80% statistical power at a two-sided significance level of 5% to detect the expected differences in endogenous thrombin potential and von Willebrand factor antigen between predefined CHA₂DS₂-VASc stroke risk groups, based on previously published effect sizes.

Continuous variables will be assessed for normality using histograms and Q-Q plots. Variables with skewed distributions will be logarithmically transformed where appropriate. Homogeneity of variances will be assessed before parametric analyses. Continuous variables will be summarized as mean ± standard deviation or median with interquartile range according to data distribution, whereas categorical variables will be summarized as frequencies and percentages.

Baseline comparisons between participants with device-detected atrial fibrillation and matched controls will be performed using appropriate parametric or non-parametric statistical methods according to data distribution. Multivariable regression models will be adjusted for predefined confounding variables as appropriate.

The prespecified baseline analyses will primarily be performed using multivariable linear regression models with endogenous thrombin potential and von Willebrand factor antigen as the primary dependent variables. Secondary analyses will evaluate associations with additional haemostatic biomarkers. Regression models will be adjusted for prespecified confounding variables. Continuous predictors will be assessed for approximate linearity, and the assumptions underlying the linear regression models will be evaluated before interpretation of the results. Sensitivity analyses will be performed to evaluate the robustness of the primary findings. Adjustment for multiple testing will be performed using the Holm-Bonferroni procedure.

Longitudinal analyses will evaluate whether baseline haemostatic biomarkers, burden of device-detected atrial fibrillation, clinical stroke risk scores, and echocardiographic findings are associated with subsequent clinical outcomes. Time-to-event analyses will be performed using Cox proportional hazards regression models when appropriate. Hazard ratios with 95% confidence intervals will be reported. Statistical significance will be defined as a two-sided p-value <0.05.

• Study Type: Observational
• Enrollment (Estimated): 222

Contacts and Locations

• Study Contact: Name: Andreas Sjøholm-Christensen, MD; Phone Number: +45 71776422; Email: andreas.sjoholm-christensen@rsyd.dk

Study Locations

• Denmark
  • Esbjerg, Denmark, 6700
    • Recruiting
    • Department of Cardiology, Esbjerg and Grindsted Hospital, Southwest Denmark
    • Contact: Andreas Sjøholm-Christensen, MD; Phone Number: +45 71776422; Email: andreas.sjoholm-christensen@rsyd.dk
    • Principal Investigator: Andreas Sjøholm-Christensen, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Participants will be recruited from the Department of Cardiology, Esbjerg and Grindsted Hospital, University Hospital of Southern Denmark. The study population comprises adults with implanted cardiac devices undergoing routine outpatient device interrogation. The device-detected atrial fibrillation cohort will include participants with at least one episode of device-detected atrial fibrillation lasting ≥1 minute identified during routine device interrogation within the previous 12 months. The control cohort will comprise participants without device-detected atrial fibrillation during the previous 4 years, recruited from the same outpatient population and matched on age, sex, and indication for cardiac device implantation. All participants will be enrolled consecutively from a single-center cardiology outpatient clinic.

Description

Inclusion Criteria:

• Age > 50 years at inclusion
• Implanted cardiac device with an atrial electrode
• ≥1 episode of device-detected atrial fibrillation lasting ≥1 minute, detected at routine cardiac device interrogation within the last 12 months
• Written informed consent obtained prior to inclusion

Exclusion Criteria:

• History of ECG-documented atrial fibrillation at any time prior to inclusion
• Use of oral anticoagulation or dual antiplatelet therapy within 6 months prior to inclusion, irrespective of indication
• Current treatment with oral contraceptives or hormone replacement therapy
• Pregnancy or breastfeeding
• End-stage renal disease (creatinine clearance <15 mL/min, calculated using the Cockcroft-Gault equation)
• Active malignancy, defined as cancer diagnosis not followed by curative treatment within 6 months of diagnosis
• Major surgery within the last 3 months
• Connective tissue disease requiring treatment
• Acute coronary syndrome, stroke/transient ischemic attack, or venous thromboembolism within 3 months prior to inclusion
• Known thrombophilia
• Clinically significant hepatic or hematological disease requiring treatment and/or specialist follow-up
• Mechanical heart valve, moderate-to-severe mitral stenosis, or other valvular disease requiring intervention

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Device-detected atrial fibrillation; Patients with implanted cardiac devices with at least one episode of device-detected atrial fibrillation lasting ≥ 1 minute within the preceding year, identified during routine device interrogation visits.
Matched controls without device-detected atrial fibrillation; Patients with implanted cardiac devices without device-detected atrial fibrillation in the preceding four years, matched 1:1 to cases on age, sex, and indication for device implantation, identified during routine device follow-up visits.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Thrombin generation assessed by endogenous thrombin potential	Thrombin generation plays a pivotal role in blood clotting and thus serve as primary outcome measure. Thrombin generation will be assessed through measurement of endogenous thrombin potential (nmol/L x min), using the calibrated automated thrombography (CAT) method.	Baseline
Levels of von Willebrand factor (vWF) antigen	von Willebrand factor plays an important role in platelet plug formation. von Willebrand factor antigen (%) will be measured using an in-house immunoassay.	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma P-selectin Concentration	Plasma concentration of soluble P-selectin antigen (ng/ml) measured using an enzyme-linked immunosorbent assay (ELISA). P-selectin will only be measured in participants with elevated von Willebrand factor antigen concentrations.	Baseline
Thrombin generation assessed by lag time	Thrombin generation plays a pivotal role in blood clotting. Thrombin generation will be assessed through measurement of lag time (min), using the calibrated automated thrombography (CAT) method.	Baseline.
Thrombin generation assessed by peak thrombin concentration	Thrombin generation plays a pivotal role in blood clotting. Thrombin generation will be assessed through measurement of peak thrombin concentration (nmol/L), using the calibrated automated thrombography (CAT) method.	Baseline
Thrombin generation assessed by time to peak	Thrombin generation plays a pivotal role in blood clotting. Thrombin generation will be assessed through measurement of time to peak (min), using the calibrated automated thrombography (CAT) method.	Baseline
Kallikrein generation assessed by lag time	Kallikrein generation plays an important role in the contact activation system of the secondary hemostasis. Kallikrein generation will be assessed through measurement of lag time (min), using the calibrated automated thrombography (CAT) method.	Baseline
High-sensitivity Cardiac Troponin T (hs-cTnT) Concentration	Plasma concentration of high-sensitivity cardiac troponin T (hs-cTnT) in ng/L measured at baseline	Baseline
Kallikrein generation assessed by peak kallikrein concentration	Kallikrein generation plays an important role in the contact activation system of the secondary hemostasis. Kallikrein generation will be assessed through measurement of peak kallikrein concentration (nmol/L), using the calibrated automated thrombography (CAT) method.	Baseline
Kallikrein generation assessed by time to peak	Kallikrein generation plays an important role in the contact activation system of the secondary hemostasis. Kallikrein generation will be assessed through measurement of time to peak (min), using the calibrated automated thrombography (CAT) method.	Baseline
Kallikrein generation assessed by endogenous kallikrein potential	Kallikrein generation plays an important role in the contact activation system of the secondary hemostasis. Kallikrein generation will be assessed through measurement of endogenous kallikrein potential (nmol/L*min), using the calibrated automated thrombography (CAT) method.	Baseline
Concentrations of prothrombin fragment 1 + 2	Activation of the inactive prothrombin to the active thrombin will be estimated from concentrations of prothrombin fragment 1 + 2 (pmol/L), using a commercial enzyme-linked immunosorbent assay (ELISA).	Baseline
Concentration of cleaved high-molecular weight kininogen (cHK)	cHK is an essential component of the contact activation system of the coagulation cascade. cHK (µg/ml) will be measured with the help of enzyme-linked immunosorbent assay (ELISA).	Baseline
Concentration of coagulation factor XII (FXII)	FXII is an essential component of the contact activation system of the coagulation cascade. FXII (µg/ml) will be measured with the help of enzyme-linked immunosorbent assay (ELISA).	Baseline
Concentration of prekallikrein	Prekallikrein is an essential component of the contact activation system of the coagulation cascade. Prekallikrein (µg/ml) will be measured with the help of enzyme-linked immunosorbent assay (ELISA).	Baseline
Concentration of high-molecular weight kininogen (HK)	HK plays a key role in the contact activation system of the coagulation cascade. HK (%) will be measured using enzyme-linked immunosorbent assay (ELISA).	Baseline
Concentration of C1-inhibitor	C1-inhibitor is the main regulator of the contact activation system. Concentration of C1-inhibitor (g/L) will be measured using nephelometry.	Baseline
Concentration of coagulation factor VII (FVII)	FVII plays an important role in the secondary hemostasis. Concentration of FVII (%) will be measured using clot assay.	Baseline
Concentration of coagulation factor X (FX)	FX plays an important role in the secondary hemostasis. Concentration of FX (%) will be measured using clot assay.	Baseline
Concentration of coagulation factor II (FII)	FII plays an important role in the secondary hemostasis. Concentration of FII (%) will be measured using clot assay.	Baseline
Concentration of protein C	Protein C is essential for the regulation of the blood coagulation cascade. Concentration of protein C (%) will be measured using chromogenic assay.	Baseline
Concentration of protein S	Protein S is essential for the regulation of the blood coagulation cascade. Concentration of protein S (%) will be measured using turbidity.	Baseline
Concentration of antithrombin (AT)	Antithrombin is essential for the regulation of the blood coagulation cascade. Concentration of antithrombin (%) will be measured using chromogenic assay.	Baseline
Concentration of tissue factor pathway inhibitor (TFPI)	TFPI is important in the regulation of the blood coagulation system. TFPI (pg/ml) will be measured using enzyme-linked immunosorbent assay (ELISA).	Baseline
Fibrin turnover assessed by maximum lysis velocity (Vmax)	Fibrin turnover will be assessed through fibrin clot lysis, where measurement of Vmax (optical density (OD)/min) will be conducted.	Baseline
Fibrin turnover assessed by peak optical density (OD)	Fibrin turnover will be assessed through fibrin clot lysis, where measurement of peak OD (OD) will be conducted.	Baseline
Fibrin turnover assessed by clot lysis	Fibrin turnover will be assessed through fibrin clot lysis, where measurement of clot lysis (%) will be conducted.	Baseline
Fibrin turnover assessed by overall hemostatic potential (OHP)	Fibrin turnover will be assessed through fibrin clot lysis, where measurement of OHP (OD x min) will be conducted.	Baseline
Fibrin turnover assessed by fiber diameter	Fibrin turnover will be assessed through fibrin clot lysis, where measurement of fiber diameter (µm) will be conducted.	Baseline
Fibrin turnover assessed by fiber density	Fibrin turnover will be assessed through fibrin clot lysis, where measurement of fiber density (x 10^6 Da/cm^3) will be conducted.	Baseline
Concentration of fibrinogen	Conversion of fibrinogen to fibrin, in which thrombin plays a key role, is essential for blood coagulation. Concentrations of fibrinogen (µmol/L) will be measured using nephelometry.	Baseline
Concentration of D-dimer	D-dimer is a fibrin degradation product that reflects the fibrinolysis process (the breakdown of fibrin network), which plays a crucial role in preventing blood clots from causing complications. D-dimer (mg/L) will be measured using immunoassay.	Baseline
Concentration of tissue-type plasminogen activator (t-PA)	t-PA is a protein that stimulates the breakdown of blood clots. It helps convert plasminogen into its active form, plasmin, the major enzyme responsible for the breakdown of blood clots. Concentration of t-PA (ng/ml) will be measured using enzyme-linked immunosorbent assay (ELISA).	Baseline
Concentration of plasminogen activator inhibitor 1 (PAI-1)	PAI-1 functions as the inhibitor of t-PA, which will stimulate the formation of blood clots. Concentration of PAI-1 (ng/ml) will be measured using enzyme-linked immunosorbent assay (ELISA).	Baseline
Levels of plasminogen	Plasminogen is the inactive form of plasmin, the major enzyme that breaks down blood clots. Levels of plasminogen (%) will be measured using chromogenic assay.	Baseline
Levels of coagulation factor XIII (FXIII)	FXIII plays a key role in stabilizing the blood clots. Levels of FXIII will be measured using immunoassay.	Baseline
Levels of plasmin inhibitor (PI)	PI is the major inhibitor of plasmin. Levels of PI (%) will be measured using chromogenic assay.	Baseline
Levels of thrombin activatable fibrinolysis inhibitor (TAFI)	TAFI is an enzyme that is activated by thrombin, which downregulates fibrinolysis, stimulating blood clot formation. Levels TAFI will be measured using enzyme-linked immunosorbent assay (ELISA).	Baseline
ADAMTS13 Antigen Concentration	Plasma concentration of ADAMTS13 antigen (ng/mL) measured using an enzyme-linked immunosorbent assay (ELISA). ADAMTS13 will only be measured in participants with elevated von Willebrand factor antigen concentrations.	Baseline
N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Concentration	Plasma concentration of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in ng/L measured at baseline.	Baseline
Stroke	Clinical stroke verified with imaging e.g. CT or MR.	Up to 10 years.
Transient Ischemic Attack	Transient Ischemic Attack verified with imaging e.g. CT or MR	Up to 10 years
Systemic embolism	Systemic embolism verified with imaging e.g. CT, MR or ultrasound	Up to 10 years
Hospitalizations	All cause hospitalizations	Up to 10 years
Heart failure hospitalizations	New onset or worsening of heart failure leading to hospitalization or urgent visit heart failure clinic	Up to 10 years
All-cause mortality	All-cause mortality	Up to 10 years
Cardiovascular death	Cardiovascular death	Up to 10 years
Progression to clinically diagnosed atrial fibrillation or atrial flutter	Atrial fibrillation or flutter verified by a 12-lead ECG or ambulatory ECG monitoring	Up to 10 years
Progression to >24 hours device-detected atrial fibrillation	Progression to >24 hours device-detected atrial fibrillation at a scheduled out-of hospital or acute cardiac device interrogation	Up to 10 years.
Initiation of oral anticoagulant therapy	Initiation of oral anticoagulant therapy with minimum 3 months treatment duration.	Up to 10 years
Pulmonary embolism	Pulmonary embolism verified with imaging e.g. CT or V/Q scan	Up to 10 years
Deep venous thrombosis	Deep venous thrombosis verified with radiology e.g. ultrasound or CT	Up to 10 years

Collaborators and Investigators

• Sponsor: Andreas Sjøholm-Christensen
• Collaborators: Region of Southern Denmark; The A.P. Moeller Foundation; Karola Jørgensens Foundation and Foundation for Cardiology in Southwest Denmark.; Grosserer L.F. Foghts Foundation; OPEN, Open Patient data Explorative Network, Odense University Hospital, Region of Southern Denmark; Sydvestjysk Kardiologisk Fond; The Simon Spies Foundation; The foundation of Fam. Kjærsgaard, Sunds
• Investigators: Principal Investigator: Andreas Sjøholm-Christensen, MD, Region of Southern Denmark

Publications and helpful links

General Publications

• Glotzer TV, Daoud EG, Wyse DG, Singer DE, Ezekowitz MD, Hilker C, Miller C, Qi D, Ziegler PD. The relationship between daily atrial tachyarrhythmia burden from implantable device diagnostics and stroke risk: the TRENDS study. Circ Arrhythm Electrophysiol. 2009 Oct;2(5):474-80. doi: 10.1161/CIRCEP.109.849638. Epub 2009 Aug 4.
• Van Gelder IC, Healey JS, Crijns HJGM, Wang J, Hohnloser SH, Gold MR, Capucci A, Lau CP, Morillo CA, Hobbelt AH, Rienstra M, Connolly SJ. Duration of device-detected subclinical atrial fibrillation and occurrence of stroke in ASSERT. Eur Heart J. 2017 May 1;38(17):1339-1344. doi: 10.1093/eurheartj/ehx042.
• Hijazi Z, Lindback J, Alexander JH, Hanna M, Held C, Hylek EM, Lopes RD, Oldgren J, Siegbahn A, Stewart RA, White HD, Granger CB, Wallentin L; ARISTOTLE and STABILITY Investigators. The ABC (age, biomarkers, clinical history) stroke risk score: a biomarker-based risk score for predicting stroke in atrial fibrillation. Eur Heart J. 2016 May 21;37(20):1582-90. doi: 10.1093/eurheartj/ehw054. Epub 2016 Feb 25.
• Thomas L, Hoy M, Byth K, Schiller NB. The left atrial function index: a rhythm independent marker of atrial function. Eur J Echocardiogr. 2008 May;9(3):356-62. doi: 10.1016/j.euje.2007.06.002. Epub 2007 Aug 7.
• Glowicki B, Matusik PT, Plens K, Undas A. Prothrombotic State in Atrial Fibrillation Patients With One Additional Risk Factor of the CHA2DS2-VASc Score (Beyond Sex). Can J Cardiol. 2019 May;35(5):634-643. doi: 10.1016/j.cjca.2019.01.014. Epub 2019 Jan 30.
• Healey JS, Connolly SJ, Gold MR, Israel CW, Van Gelder IC, Capucci A, Lau CP, Fain E, Yang S, Bailleul C, Morillo CA, Carlson M, Themeles E, Kaufman ES, Hohnloser SH; ASSERT Investigators. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med. 2012 Jan 12;366(2):120-9. doi: 10.1056/NEJMoa1105575.
• Svendsen JH, Diederichsen SZ, Hojberg S, Krieger DW, Graff C, Kronborg C, Olesen MS, Nielsen JB, Holst AG, Brandes A, Haugan KJ, Kober L. Implantable loop recorder detection of atrial fibrillation to prevent stroke (The LOOP Study): a randomised controlled trial. Lancet. 2021 Oct 23;398(10310):1507-1516. doi: 10.1016/S0140-6736(21)01698-6. Epub 2021 Aug 29.
• Kundrick J, Saba KI, Naniwadekar A, Singla V, Mulukutla S, Thoma F, Bhonsale A, Kancharla K, Voigt A, Shalaby AA, Estes Iii NAM, Jain S, Saba S. Diastolic Dysfunction and the Risk of Stroke and Major Bleeding. Stroke. 2024 Dec;55(12):2856-2862. doi: 10.1161/STROKEAHA.124.048287. Epub 2024 Nov 11.
• Suwa Y, Miyasaka Y, Taniguchi N, Harada S, Nakai E, Shiojima I. Atrial fibrillation and stroke: importance of left atrium as assessed by echocardiography. J Echocardiogr. 2022 Jun;20(2):69-76. doi: 10.1007/s12574-021-00561-6. Epub 2022 Jan 23.
• Alonso A, Tang W, Agarwal SK, Soliman EZ, Chamberlain AM, Folsom AR. Hemostatic markers are associated with the risk and prognosis of atrial fibrillation: the ARIC study. Int J Cardiol. 2012 Mar 8;155(2):217-22. doi: 10.1016/j.ijcard.2010.09.051. Epub 2010 Oct 20.
• Wu N, Chen X, Cai T, Wu L, Xiang Y, Zhang M, Li Y, Song Z, Zhong L. Association of inflammatory and hemostatic markers with stroke and thromboembolic events in atrial fibrillation: a systematic review and meta-analysis. Can J Cardiol. 2015 Mar;31(3):278-86. doi: 10.1016/j.cjca.2014.12.002. Epub 2014 Dec 9.
• Undas A. Altered fibrin clot properties and fibrinolysis in patients with atrial fibrillation: practical implications. Europace. 2020 Feb 1;22(2):185-194. doi: 10.1093/europace/euz271.
• Becher N, Toennis T, Bertaglia E, Blomstrom-Lundqvist C, Brandes A, Cabanelas N, Calvert M, Camm AJ, Chlouverakis G, Dan GA, Dichtl W, Diener HC, Fierenz A, Goette A, de Groot JR, Hermans ANL, Lip GYH, Lubinski A, Marijon E, Merkely B, Mont L, Ozga AK, Rajappan K, Sarkozy A, Scherr D, Schnabel RB, Schotten U, Sehner S, Simantirakis E, Vardas P, Velchev V, Wichterle D, Zapf A, Kirchhof P. Anticoagulation with edoxaban in patients with long atrial high-rate episodes >/=24 h. Eur Heart J. 2024 Mar 7;45(10):837-849. doi: 10.1093/eurheartj/ehad771.
• McIntyre WF, Benz AP, Healey JS, Connolly SJ, Yang M, Lee SF, Field TS, Alings M, Benezet-Mazuecos J, Boriani G, Nielsen JC, Gold MR, Pergolini F, Glotzer TV, Granger CB, Lopes RD. Risk of Stroke or Systemic Embolism According to Baseline Frequency and Duration of Subclinical Atrial Fibrillation: Insights From the ARTESiA Trial. Circulation. 2024 Nov 26;150(22):1747-1755. doi: 10.1161/CIRCULATIONAHA.124.069903. Epub 2024 Sep 4.
• McIntyre WF, Benz AP, Becher N, Healey JS, Granger CB, Rivard L, Camm AJ, Goette A, Zapf A, Alings M, Connolly SJ, Kirchhof P, Lopes RD. Direct Oral Anticoagulants for Stroke Prevention in Patients With Device-Detected Atrial Fibrillation: A Study-Level Meta-Analysis of the NOAH-AFNET 6 and ARTESiA Trials. Circulation. 2024 Mar 26;149(13):981-988. doi: 10.1161/CIRCULATIONAHA.123.067512. Epub 2023 Nov 12.
• Schnabel RB, Benezet-Mazuecos J, Becher N, McIntyre WF, Fierenz A, Lee SF, Goette A, Atar D, Bertaglia E, Benz AP, Chlouverakis G, Birnie DH, Dichtl W, Blomstrom-Lundqvist C, Camm AJ, Erath JW, Simantirakis E, Kutyifa V, Lip GYH, Mabo P, Marijon E, Rivard L, Schotten U, Alings M, Sehner S, Toennis T, Linde C, Vardas P, Granger CB, Zapf A, Lopes RD, Healey JS, Kirchhof P. Anticoagulation in device-detected atrial fibrillation with or without vascular disease: a combined analysis of the NOAH-AFNET 6 and ARTESiA trials. Eur Heart J. 2024 Dec 7;45(46):4902-4916. doi: 10.1093/eurheartj/ehae596.
• Lopes RD, Granger CB, Wojdyla DM, McIntyre WF, Alings M, Mani T, Ramasundarahettige C, Rivard L, Atar D, Birnie DH, Boriani G, Amit G, Leong-Sit P, Rinne C, Duray GZ, Gold MR, Hohnloser SH, Kutyifa V, Benezet-Mazuecos J, Cosedis Nielsen J, Sticherling C, Benz AP, Linde C, Kautzner J, Mabo P, Mairesse GH, Connolly SJ, Healey JS. Apixaban vs Aspirin According to CHA2DS2-VASc Score in Subclinical Atrial Fibrillation: Insights From ARTESiA. J Am Coll Cardiol. 2024 Jul 23;84(4):354-364. doi: 10.1016/j.jacc.2024.05.002. Epub 2024 May 19.
• Healey JS, Lopes RD, Granger CB, Alings M, Rivard L, McIntyre WF, Atar D, Birnie DH, Boriani G, Camm AJ, Conen D, Erath JW, Gold MR, Hohnloser SH, Ip J, Kautzner J, Kutyifa V, Linde C, Mabo P, Mairesse G, Benezet Mazuecos J, Cosedis Nielsen J, Philippon F, Proietti M, Sticherling C, Wong JA, Wright DJ, Zarraga IG, Coutts SB, Kaplan A, Pombo M, Ayala-Paredes F, Xu L, Simek K, Nevills S, Mian R, Connolly SJ; ARTESIA Investigators. Apixaban for Stroke Prevention in Subclinical Atrial Fibrillation. N Engl J Med. 2024 Jan 11;390(2):107-117. doi: 10.1056/NEJMoa2310234. Epub 2023 Nov 12.
• Kirchhof P, Toennis T, Goette A, Camm AJ, Diener HC, Becher N, Bertaglia E, Blomstrom Lundqvist C, Borlich M, Brandes A, Cabanelas N, Calvert M, Chlouverakis G, Dan GA, de Groot JR, Dichtl W, Kravchuk B, Lubinski A, Marijon E, Merkely B, Mont L, Ozga AK, Rajappan K, Sarkozy A, Scherr D, Sznajder R, Velchev V, Wichterle D, Sehner S, Simantirakis E, Lip GYH, Vardas P, Schotten U, Zapf A; NOAH-AFNET 6 Investigators; NOAH-AFNET6 sites and investigators. Anticoagulation with Edoxaban in Patients with Atrial High-Rate Episodes. N Engl J Med. 2023 Sep 28;389(13):1167-1179. doi: 10.1056/NEJMoa2303062. Epub 2023 Aug 25.

Study record dates

Study Major Dates

• Study Start (Actual): February 27, 2026
• Primary Completion (Estimated): February 1, 2029
• Study Completion (Estimated): September 1, 2037

Study Registration Dates

• First Submitted: July 8, 2026
• First Submitted That Met QC Criteria: July 14, 2026
• First Posted (Actual): July 20, 2026

Study Record Updates

• Last Update Posted (Actual): July 20, 2026
• Last Update Submitted That Met QC Criteria: July 14, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Biomarkers; Atrial fibrillation burden; Echocardiography; Thromboembolism; Oral anticoagulation; Haemostasis; Thrombin generation; Cardiac implantable electronic devices; von Willebrand factor; Stroke risk; Left atrial function; ABC-stroke score; CHA₂DS₂-VASc; CHA₂DS₂-VA
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Embolism and Thrombosis; Thromboembolism
• Other Study ID Numbers: 116655

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be shared publicly due to privacy regulations and ethical restrictions. Aggregated data will be reported in publications.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No